Endometrial Carcinoma: Specific Targeted Pathways

  • Nuria Eritja
  • Andree Yeramian
  • Bo-Juen Chen
  • David Llobet-Navas
  • Eugenia Ortega
  • Eva Colas
  • Miguel Abal
  • Xavier Dolcet
  • Jaume Reventos
  • Xavier Matias-Guiu
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 943)


Endometrial cancer (EC) is the most common gynecologic malignancy in the western world with more than 280,000 cases per year worldwide. Prognosis for EC at early stages, when primary surgical resection is the most common initial treatment, is excellent. Five-year survival rate is around 70 %.

Several molecular alterations have been described in the different types of EC. They occur in genes involved in important signaling pathways. In this chapter, we will review the most relevant altered pathways in EC, including PI3K/AKT/mTOR, RAS–RAF–MEK–ERK, Tyrosine kinase, WNT/β-Catenin, cell cycle, and TGF-β signaling pathways. At the end of the chapter, the most significant clinical trials will be briefly discussed.

This information is important to identify specific targets for therapy.


Endometrial cancer Signaling pathway Target therapies PI3K pathology 


  1. 1.
    DI Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998;19:348–55.PubMedGoogle Scholar
  2. 2.
    Eritja N, Mirantes C, Llobet D, Yeramian A, Bergadà L, Dosil MA, Domingo M, Matias-Guiu X, Dolcet X. Long-term estradiol exposure is a direct mitogen for insulin/EGF-primed endometrial cells and drives PTEN loss-induced hyperplasic growth. Am J Pathol. 2013;183:277–87.PubMedGoogle Scholar
  3. 3.
    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O’Brien P, Boisvert JL, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovic I, Engelman JA, Sharma SV, Delattre O, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U, Benes CH. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–5.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Mirantes C, Eritja N, Dosil MA, Santacana M, Pallares J, Gatius S, Bergadà L, Maiques O, Matias-Guiu X, Dolcet X. An inducible knockout mouse to model the cell-autonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias. Dis Model Mech. 2013;6:710–20.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Velasco A, Bussaglia E, Pallares J, Dolcet X, Llobet D, Encinas M, Llecha N, Palacios J, Prat J, Matias-Guiu X. PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations. Hum Pathol. 2006;37:1465–72.PubMedGoogle Scholar
  6. 6.
    Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28:1075–83.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.PubMedGoogle Scholar
  8. 8.
    Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7:261–9.PubMedGoogle Scholar
  9. 9.
    Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615–75.PubMedGoogle Scholar
  10. 10.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.PubMedGoogle Scholar
  11. 11.
    Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 1999;24:186–91.PubMedGoogle Scholar
  12. 12.
    Juric D, Castel P, Griffith M, Griffith OL, Won HH, Ellis H, Ebbesen SH, Ainscough BJ, Ramu A, Iyer G, Shah RH, Huynh T, Mino-Kenudson M, Sgroi D, Isakoff S, Thabet A, Elamine L, Solit DB, Lowe SW, Quadt C, Peters M, Derti A, Schegel R, Huang A, Mardis ER, Berger MF, Baselga J, Scaltriti M. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2014;518:240–4.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA, Network CGAR. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.PubMedGoogle Scholar
  14. 14.
    Bonneau D, Longy M. Mutations of the human PTEN gene. Hum Mutat. 2000;16:109–22.PubMedGoogle Scholar
  15. 15.
    Eritja N, Santacana M, Maiques O, Gonzalez-Tallada X, Dolcet X, Matias-Guiu X. Modeling glands with PTEN deficient cells and microscopic methods for assessing PTEN loss: endometrial cancer as a model. Methods. 2015;77–78:31–40.PubMedGoogle Scholar
  16. 16.
    Lacey JV, Mutter GL, Ronnett BM, Ioffe OB, Duggan MA, Rush BB, Glass AG, Richesson DA, Chatterjee N, Langholz B, Sherman ME. PTEN expression in endometrial biopsies as a marker of progression to endometrial carcinoma. Cancer Res. 2008;68:6014–20.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP, Eng C. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92:924–30.PubMedGoogle Scholar
  18. 18.
    Prat J, Gallardo A, Cuatrecasas M, Catasus L. Endometrial carcinoma: pathology and genetics. Pathology. 2007;39:72–87.PubMedGoogle Scholar
  19. 19.
    Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, Ellenson LH. PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res. 2006;12:5932–5.PubMedGoogle Scholar
  20. 20.
    Markowska A, Pawałowska M, Lubin J, Markowska J. Signalling pathways in endometrial cancer. Contemp Oncol (Pozn). 2014;18:143–8.Google Scholar
  21. 21.
    Djordjevic B, Barkoh BA, Luthra R, Broaddus RR. Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas. Mod Pathol. 2013;26:1401–12.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Catasus L, Gallardo A, Cuatrecasas M, Prat J. PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod Pathol. 2008;21:131–9.PubMedGoogle Scholar
  23. 23.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.PubMedGoogle Scholar
  24. 24.
    Moreno-Bueno G, Hardisson D, Sarrio D, Sanchez C, Cassia R, Prat J, Herman JG, Esteller M, Matias-Guiu X, Palacios J. Abnormalities of E- and P-cadherin and catenin (beta-, gamma-catenin, and p120ctn) expression in endometrial cancer and endometrial atypical hyperplasia. J Pathol. 2003;199:471–8.PubMedGoogle Scholar
  25. 25.
    Rudd ML, Price JC, Fogoros S, Godwin AK, Sgroi DC, Merino MJ, Bell DW. A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas. Clin Cancer Res. 2011;17:1331–40.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005;65:10669–73.PubMedGoogle Scholar
  27. 27.
    Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, Lu Y, Stemke-Hale K, Dyer MD, Zhang F, Ju Z, Cantley LC, Scherer SE, Liang H, Lu KH, Broaddus RR, Mills GB. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1:170–85.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 2011;71:4061–7.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Shoji K, Oda K, Nakagawa S, Hosokawa S, Nagae G, Uehara Y, Sone K, Miyamoto Y, Hiraike H, Hiraike-Wada O, Nei T, Kawana K, Kuramoto H, Aburatani H, Yano T, Taketani Y. The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer. 2009;101:145–8.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–91.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Karamurzin Y, Rutgers JK. DNA mismatch repair deficiency in endometrial carcinoma. Int J Gynecol Pathol. 2009;28:239–55.PubMedGoogle Scholar
  32. 32.
    Pavlidou A, Vlahos NF. Molecular alterations of PI3K/Akt/mTOR pathway: a therapeutic target in endometrial cancer. ScientificWorldJournal. 2014;2014:709736.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Lu KH, Wu W, Dave B, Slomovitz BM, Burke TW, Munsell MF, Broaddus RR, Walker CL. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res. 2008;14:2543–50.PubMedGoogle Scholar
  34. 34.
    Gentilini D, Busacca M, DI Francesco S, Vignali M, Viganò P, DI Blasio AM. PI3K/Akt and ERK1/2 signalling pathways are involved in endometrial cell migration induced by 17beta-estradiol and growth factors. Mol Hum Reprod. 2007;13:317–22.PubMedGoogle Scholar
  35. 35.
    Tang LL, Yokoyama Y, Wan X, Iwagaki S, Niwa K, Tamaya T. PTEN sensitizes epidermal growth factor-mediated proliferation in endometrial carcinoma cells. Oncol Rep. 2006;15:855–9.PubMedGoogle Scholar
  36. 36.
    Vivacqua A, Bonofiglio D, Recchia AG, Musti AM, Picard D, Andò S, Maggiolini M. The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol. 2006;20:631–46.PubMedGoogle Scholar
  37. 37.
    Guo RX, Zhang RF, Wang XY, Shi HR, Qiao YH. Effects of PD98059 and LY294002 on subcutaneous xenograft of human endometrial carcinoma in nude mice. Zhonghua Fu Chan Ke Za Zhi. 2011;46:446–52.PubMedGoogle Scholar
  38. 38.
    Eritja N, Llobet D, Domingo M, Santacana M, Yeramian A, Matias-Guiu X, Dolcet X. A novel three-dimensional culture system of polarized epithelial cells to study endometrial carcinogenesis. Am J Pathol. 2010;176:2722–31.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Bradford LS, Rauh-Hain A, Clark RM, Groeneweg JW, Zhang L, Borger D, Zukerberg LR, Growdon WB, Foster R, Rueda BR. Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer. Gynecol Oncol. 2014;133:346–52.PubMedGoogle Scholar
  40. 40.
    Weigelt B, Warne PH, Lambros MB, Reis-Filho JS, Downward J. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res. 2013;19:3533–44.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Cheng H, Liu P, Zhang F, Xu E, Symonds L, Ohlson CE, Bronson RT, Maira SM, Di Tomaso E, Li J, Myers AP, Cantley LC, Mills GB, Zhao JJ. A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Res. 2014;74:15–23.PubMedGoogle Scholar
  42. 42.
    Weigelt B, Bissell MJ. Unraveling the microenvironmental influences on the normal mammary gland and breast cancer. Semin Cancer Biol. 2008;18:311–21.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Erdemoglu E, Güney M, Take G, Giray SG, Mungan T. RAD001 (Everolimus) Can prevent tamoxifen-related endometrial and stromal hyperplasia. Int J Gynecol Cancer. 2009;19:375–9.PubMedGoogle Scholar
  44. 44.
    Milam MR, Celestino J, Wu W, Broaddus RR, Schmeler KM, Slomovitz BM, Soliman PT, Gershenson DM, Wang H, Ellenson LH, Lu KH. Reduced progression of endometrial hyperplasia with oral mTOR inhibition in the Pten heterozygote murine model. Am J Obstet Gynecol. 2007;196:247.e15.Google Scholar
  45. 45.
    Lu XY, Yang Y, Xu H, Zeng T, Zhang ZZ. Synergistic in vitro anti-tumor effect of letrozole and everolimus on human endometrial carcinoma Ishikawa cells. Eur Rev Med Pharmacol Sci. 2014;18:2264–9.PubMedGoogle Scholar
  46. 46.
    Korets SB, Musa F, Curtin J, Blank SV, Schneider RJ. Dual mTORC1/2 inhibition in a preclinical xenograft tumor model of endometrial cancer. Gynecol Oncol. 2014;132:468–73.PubMedGoogle Scholar
  47. 47.
    Block M, Fister S, Emons G, Seeber S, Grundker C, Gunthert AR. Antiproliferative effects of antiestrogens and inhibitors of growth factor receptor signaling on endometrial cancer cells. Anticancer Res. 2010;30:2025–31.PubMedGoogle Scholar
  48. 48.
    Kharma B, Baba T, Mandai M, Matsumura N, Murphy SK, Kang HS, Yamanoi K, Hamanishi J, Yamaguchi K, Yoshioka Y, Konishi I. Utilization of genomic signatures to identify high-efficacy candidate drugs for chemorefractory endometrial cancers. Int J Cancer. 2013;133:2234–44.PubMedGoogle Scholar
  49. 49.
    Gozgit JM, Squillace RM, Wongchenko MJ, Miller D, Wardwell S, Mohemmad Q, Narasimhan NI, Wang F, Clackson T, Rivera VM. Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother Pharmacol. 2013;71:1315–23.PubMedGoogle Scholar
  50. 50.
    Squillace RM, Miller D, Cookson M, Wardwell SD, Moran L, Clapham D, Wang F, Clackson T, Rivera VM. Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther. 2011;10:1959–68.PubMedGoogle Scholar
  51. 51.
    Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, James D, Howard Z, Dudley P, Hughes G, Smith L, Maguire S, Hummersone M, Malagu K, Menear K, Jenkins R, Jacobsen M, Smith GC, Guichard S, Pass M. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70:288–98.PubMedGoogle Scholar
  52. 52.
    English DP, Roque DM, Carrara L, Lopez S, Bellone S, Cocco E, Bortolomai I, Schwartz PE, Rutherford T, Santin AD. HER2/neu gene amplification determines the sensitivity of uterine serous carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor. Gynecol Oncol. 2013;131:753–8.PubMedGoogle Scholar
  53. 53.
    Shoji K, Oda K, Kashiyama T, Ikeda Y, Nakagawa S, Sone K, Miyamoto Y, Hiraike H, Tanikawa M, Miyasaka A, Koso T, Matsumoto Y, Wada-Hiraike O, Kawana K, Kuramoto H, McCormick F, Aburatani H, Yano T, Kozuma S, Taketani Y. Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. PLoS One. 2012;7:e37431.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Engel JB, Honig A, Schönhals T, Weidler C, Häusler S, Krockenberger M, Grunewald TG, Dombrowski Y, Rieger L, Dietl J, Wischhusen J. Perifosine inhibits growth of human experimental endometrial cancers by blockade of AKT phosphorylation. Eur J Obstet Gynecol Reprod Biol. 2008;141:64–9.PubMedGoogle Scholar
  55. 55.
    Pant A, Lee II, Lu Z, Rueda BR, Schink J, Kim JJ. Inhibition of AKT with the orally active allosteric AKT inhibitor, MK-2206, sensitizes endometrial cancer cells to progestin. PLoS One. 2012;7:e41593.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Gray MJ, Mhawech-Fauceglia P, Yoo E, Yang W, Wu E, Lee AS, Lin YG. AKT inhibition mitigates GRP78 (glucose-regulated protein) expression and contribution to chemoresistance in endometrial cancers. Int J Cancer. 2013;133:21–30.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Knight ZA, Shokat KM. Chemically targeting the PI3K family. Biochem Soc Trans. 2007;35:245–9.PubMedGoogle Scholar
  58. 58.
    Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chène P, Shoemaker K, DE Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, García-Echeverría C, Sellers WR, Voliva CF. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11:317–28.PubMedGoogle Scholar
  59. 59.
    Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, Kugendradas A, Lensun L, Moore P, Olivero AG, Pang J, Patel S, Pergl-Wilson GH, Raynaud FI, Robson A, Saghir N, Salphati L, Sohal S, Ultsch MH, Valenti M, Wallweber HJ, Wan NC, Wiesmann C, Workman P, Zhyvoloup A, Zvelebil MJ, Shuttleworth SJ. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008;51:5522–32.PubMedGoogle Scholar
  60. 60.
    Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, Stückrath I, Weiss J, Fischer F, Michel K, Goel A, Regales L, Politi KA, Perera S, Getlik M, Heukamp LC, Ansén S, Zander T, Beroukhim R, Kashkar H, Shokat KM, Sellers WR, Rauh D, Orr C, Hoeflich KP, Friedman L, Wong KK, Pao W, Thomas RK. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci U S A. 2009;106:18351–6.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Brachmann SM, Kleylein-Sohn J, Gaulis S, Kauffmann A, Blommers MJ, Kazic-Legueux M, Laborde L, Hattenberger M, Stauffer F, Vaxelaire J, Romanet V, Henry C, Murakami M, Guthy DA, Sterker D, Bergling S, Wilson C, Brümmendorf T, Fritsch C, Garcia-Echeverria C, Sellers WR, Hofmann F, Maira SM. Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations. Mol Cancer Ther. 2012;11:1747–57.PubMedGoogle Scholar
  62. 62.
    Slomovitz BM, Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. 2012;18:5856–64.PubMedGoogle Scholar
  63. 63.
    Macias-Perez IM, Flinn IW. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2013;8:22–7.PubMedGoogle Scholar
  64. 64.
    Wang X, Yue P, Chan CB, Ye K, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Fu H, Khuri FR, Sun SY. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Mol Cell Biol. 2007;27:7405–13.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, DE Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, García-Echeverría C. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7:1851–63.PubMedGoogle Scholar
  66. 66.
    Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, Salphati L, Olivero AG, Sutherlin DP, O’Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011;10:2426–36.PubMedGoogle Scholar
  67. 67.
    Ai Z, Wang J, Wang Y, Lu L, Tong J, Teng Y. Overexpressed epidermal growth factor receptor (EGFR)-induced progestin insensitivity in human endometrial carcinoma cells by the EGFR/mitogen-activated protein kinase signaling pathway. Cancer. 2010;116:3603–13.PubMedGoogle Scholar
  68. 68.
    Rouette A, Parent S, Girouard J, Leblanc V, Asselin E. Cisplatin increases B-cell-lymphoma-2 expression via activation of protein kinase C and Akt2 in endometrial cancer cells. Int J Cancer. 2012;130:1755–67.PubMedGoogle Scholar
  69. 69.
    Terakawa N, Kanamori Y, Yoshida S. Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer. Endocr Relat Cancer. 2003;10:203–8.PubMedGoogle Scholar
  70. 70.
    Plotnikov A, Zehorai E, Procaccia S, Seger R. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta. 2011;1813:1619–33.PubMedGoogle Scholar
  71. 71.
    Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9:517–31.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129:865–77.PubMedGoogle Scholar
  73. 73.
    Cherfils J, Zeghouf M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev. 2013;93:269–309.PubMedGoogle Scholar
  74. 74.
    Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10:842–57.PubMedPubMedCentralGoogle Scholar
  75. 75.
    An S, Yang Y, Ward R, Liu Y, Guo X-X, Xu T-R. Raf-interactome in tuning the complexity and diversity of Raf function. FEBS J. 2015;282:32–53.PubMedGoogle Scholar
  76. 76.
    Cseh B, Doma E, Baccarini M. “RAF” neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway. FEBS Lett. 2014;588:2398–406.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Roskoski R. MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem Biophys Res Commun. 2012;417:5–10.PubMedGoogle Scholar
  78. 78.
    Roskoski R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66:105–43.PubMedGoogle Scholar
  79. 79.
    Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci U S A. 1982;79:3637–40.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Parada LF, Tabin CJ, Shih C, Weinberg RA. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature. 1982;297:474–8.PubMedGoogle Scholar
  82. 82.
    Santos E, Tronick SR, Aaronson SA, Pulciani S, Barbacid M. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature. 1982;298:343–7.PubMedGoogle Scholar
  83. 83.
    Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature. 1982;300:762–5.PubMedGoogle Scholar
  84. 84.
    Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457–67.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Quinlan MP, Settleman J. Isoform-specific ras functions in development and cancer. Future Oncol. 2009;5:105–16.PubMedGoogle Scholar
  86. 86.
    Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7:295–308.PubMedGoogle Scholar
  87. 87.
    Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25:272–81.PubMedGoogle Scholar
  88. 88.
    Holderfield M, Deuker MM, McCormick F, Mcmahon M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 2014;14:455–67.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Enomoto T, Inoue M, Perantoni AO, Buzard GS, Miki H, Tanizawa O, Rice JM. K-ras activation in premalignant and malignant epithelial lesions of the human uterus. Cancer Res. 1991;51:5308–14.PubMedGoogle Scholar
  90. 90.
    Enomoto T, Inoue M, Perantoni AO, Terakawa N, Tanizawa O, Rice JM. K-ras activation in neoplasms of the human female reproductive tract. Cancer Res. 1990;50:6139–45.PubMedGoogle Scholar
  91. 91.
    Lester DR, Cauchi MN. Point mutations at codon 12 of C-K-ras in human endometrial carcinomas. Cancer Lett. 1990;51:7–10.PubMedGoogle Scholar
  92. 92.
    Caduff RF, Johnston CM, Frank TS. Mutations of the Ki-ras oncogene in carcinoma of the endometrium. Am J Pathol. 1995;146:182–8.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Duggan BD, Felix JC, Muderspach LI, Tsao JL, Shibata DK. Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma. Cancer Res. 1994;54:1604–7.PubMedGoogle Scholar
  94. 94.
    Hruban RH, VAN Mansfeld AD, Offerhaus GJ, VAN Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143:545–54.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Ignar-Trowbridge D, Risinger JI, Dent GA, Kohler M, Berchuck A, Mclachlan JA, Boyd J. Mutations of the Ki-ras oncogene in endometrial carcinoma. Am J Obstet Gynecol. 1992;167:227–32.PubMedGoogle Scholar
  96. 96.
    Lagarda H, Catasus L, Arguelles R, Matias-Guiu X, Prat J. K-ras mutations in endometrial carcinomas with microsatellite instability. J Pathol. 2001;193:193–9.PubMedGoogle Scholar
  97. 97.
    Sasaki H, Nishii H, Takahashi H, Tada A, Furusato M, Terashima Y, Siegal GP, Parker SL, Kohler MF, Berchuck A. Mutation of the Ki-ras protooncogene in human endometrial hyperplasia and carcinoma. Cancer Res. 1993;53:1906–10.PubMedGoogle Scholar
  98. 98.
    Moreno-Bueno G, Sanchez-Estevez C, Palacios J, Hardisson D, Shiozawa T. Low frequency of BRAF mutations in endometrial and in cervical carcinomas. Clin Cancer Res. 2006;12:3865. author reply 3865–6.PubMedGoogle Scholar
  99. 99.
    Pappa KI, Choleza M, Markaki S, Giannikaki E, Kyroudi A, Vlachos G, Voulgaris Z, Anagnou NP. Consistent absence of BRAF mutations in cervical and endometrial cancer despite KRAS mutation status. Gynecol Oncol. 2006;100:596–600.PubMedGoogle Scholar
  100. 100.
    Salvesen HB, Kumar R, Stefansson I, Angelini S, MacDonald N, Smeds J, Jacobs IJ, Hemminki K, Das S, Akslen LA. Low frequency of BRAF and CDKN2A mutations in endometrial cancer. Int J Cancer. 2005;115:930–4.PubMedGoogle Scholar
  101. 101.
    Ueda M, Toji E, Nunobiki O, Izuma S, Okamoto Y, Torii K, Noda S. Mutational analysis of the BRAF gene in human tumor cells. Hum Cell. 2008;21:13–7.PubMedGoogle Scholar
  102. 102.
    Kang S, Lee JM, Jeon E-S, Lee S, Kim H, Kim H-S, Seo S-S, Park S-Y, Sidransky D, Dong SM. RASSF1A hypermethylation and its inverse correlation with BRAF and/or KRAS mutations in MSI-associated endometrial carcinoma. Int J Cancer. 2006;119:1316–21.PubMedGoogle Scholar
  103. 103.
    Liao X, Siu MK-Y, Chan KY-K, Wong ES-Y, Ngan HY-S, Chan QK-Y, Li AS-M, Khoo U-S, Cheung AN-Y. Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis. Int J Cancer. 2008;123:296–302.PubMedGoogle Scholar
  104. 104.
    Pallares J, Velasco A, Eritja N, Santacana M, Dolcet X, Cuatrecasas M, Palomar-Asenjo V, Catasus L, Prat J, Matias-Guiu X. Promoter hypermethylation and reduced expression of RASSF1A are frequent molecular alterations of endometrial carcinoma. Mod Pathol. 2008;21:691–9.PubMedGoogle Scholar
  105. 105.
    Pijnenborg JMA, Dam-De Veen GC, Kisters N, Delvoux B, Van Engeland M, Herman JG, Groothuis PG. RASSF1A methylation and K-ras and B-raf mutations and recurrent endometrial cancer. Ann Oncol. 2007;18:491–7.PubMedGoogle Scholar
  106. 106.
    Velasco A, Pallares J, Santacana M, Gatius S, Fernandez M, Domingo M, Valls J, Yeramian A, Encinas M, Dolcet X, Matias-Guiu X. Promoter hypermethylation and expression of sprouty 2 in endometrial carcinoma. Hum Pathol. 2011;42:185–93.PubMedGoogle Scholar
  107. 107.
    Llobet D, Eritja N, Domingo M, Bergada L, Mirantes C, Santacana M, Pallares J, Macià A, Yeramian A, Encinas M, Moreno-Bueno G, Palacios J, Lewis RE, Matias-Guiu X, Dolcet X. KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels. Am J Pathol. 2011;178:1529–43.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Mizumoto Y, Kyo S, Ohno S, Hashimoto M, Nakamura M, Maida Y, Sakaguchi J, Takakura M, Inoue M, Kiyono T. Creation of tumorigenic human endometrial epithelial cells with intact chromosomes by introducing defined genetic elements. Oncogene. 2006;25:5673–82.PubMedGoogle Scholar
  109. 109.
    Watanabe T, Kashida Y, Yasuhara K, Koujitani T, Hirose M, Mitsumori K. Rapid induction of uterine endometrial proliferative lesions in transgenic mice carrying a human prototype c-Ha-ras gene (rasH2 mice) given a single intraperitoneal injection of N-ethyl-N-nitrosourea. Cancer Lett. 2002;188:39–46.PubMedGoogle Scholar
  110. 110.
    Kim TH, Wang J, Lee KY, Franco HL, Broaddus RR, Lydon JP, Jeong J-W, Demayo FJ. The synergistic effect of conditional Pten loss and oncogenic K-ras mutation on endometrial cancer development occurs via decreased progesterone receptor action. J Oncol. 2010;2010:139087.PubMedGoogle Scholar
  111. 111.
    Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014;13:928–42.PubMedGoogle Scholar
  112. 112.
    Little AS, Smith PD, Cook SJ. Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Oncogene. 2013;32:1207–15.PubMedGoogle Scholar
  113. 113.
    Miller CR, Oliver KE, Farley JH. MEK1/2 inhibitors in the treatment of gynecologic malignancies. Gynecol Oncol. 2014;133:128–37.PubMedGoogle Scholar
  114. 114.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–34.PubMedGoogle Scholar
  115. 115.
    Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Krause DS, VAN Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172–87.PubMedGoogle Scholar
  117. 117.
    Robertson SC, Tynan J, Donoghue DJ. RTK mutations and human syndromes: when good receptors turn bad. Trends Genet. 2000;16:368.PubMedGoogle Scholar
  118. 118.
    Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer. 2004;4:361–70.PubMedGoogle Scholar
  119. 119.
    Hunter T. The Croonian Lecture 1997. The phosphorylation of proteins on tyrosine: its role in cell growth and disease. Philos Trans R Soc Lond B Biol Sci. 1998;353:583–605.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, Goodfellow PJ, Pollock PM. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLoS One. 2012;7:e30801.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Weiner DB, Liu J, Cohen JA, Williams WV, Greene MI. A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature. 1989;339:230–1.PubMedGoogle Scholar
  122. 122.
    Wang R, Kobayashi R, Bishop JM. Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor. Proc Natl Acad Sci U S A. 1996;93:8425–30.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem. 1999;274:8865–74.PubMedGoogle Scholar
  124. 124.
    Zhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, Guzzo F, English DP, Varughese J, Gasparrini S, Bortolomai I, Buza N, Hui P, Abu-Khalaf M, Ravaggi A, Bignotti E, Bandiera E, Romani C, Todeschini P, Tassi R, Zanotti L, Carrara L, Pecorelli S, Silasi DA, Ratner E, Azodi M, Schwartz PE, Rutherford TJ, Stiegler AL, Mane S, Boggon TJ, Schlessinger J, Lifton RP, Santin AD. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A. 2013;110:2916–21.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Albitar L, Carter MB, Davies S, Leslie KK. Consequences of the loss of p53, RB1, and PTEN: relationship to gefitinib resistance in endometrial cancer. Gynecol Oncol. 2007;106:94–104.PubMedGoogle Scholar
  126. 126.
    Gaikwad A, Wolf JK, Brown J, Ramondetta LM, Smith JA. In vitro evaluation of the effects of gefitinib on the cytotoxic activity of selected anticancer agents in a panel of human endometrial cancer cell lines. J Oncol Pharm Pract. 2009;15:35–44.PubMedGoogle Scholar
  127. 127.
    Xu Y, Tong J, Ai Z, Wang J, Teng Y. Epidermal growth factor receptor signaling pathway involved in progestin-resistance of human endometrial carcinoma: in a mouse model. J Obstet Gynaecol Res. 2012;38:1358–66.PubMedGoogle Scholar
  128. 128.
    Chen CH, Wang SW, Chen CW, Huang MR, Hung JS, Huang HC, Lin HH, Chen RJ, Shyu MK, Huang MC. MUC20 overexpression predicts poor prognosis and enhances EGF-induced malignant phenotypes via activation of the EGFR-STAT3 pathway in endometrial cancer. Gynecol Oncol. 2013;128:560–7.PubMedGoogle Scholar
  129. 129.
    Takahashi K, Saga Y, Mizukami H, Takei Y, Machida S, Fujiwara H, Ozawa K, Suzuki M. Cetuximab inhibits growth, peritoneal dissemination, and lymph node and lung metastasis of endometrial cancer, and prolongs host survival. Int J Oncol. 2009;35:725–9.PubMedGoogle Scholar
  130. 130.
    Pfeiler G, Horn F, Lattrich C, Klappenberger S, Ortmann O, Treeck O. Apoptotic effects of signal transduction inhibitors on human tumor cells with different PTEN expression. Oncol Rep. 2007;18:1305–9.PubMedGoogle Scholar
  131. 131.
    Treeck O, Diedrich K, Ortmann O. The activation of an extracellular signal-regulated kinase by oestradiol interferes with the effects of trastuzumab on HER2 signalling in endometrial adenocarcinoma cell lines. Eur J Cancer. 2003;39:1302–9.PubMedGoogle Scholar
  132. 132.
    El-Sahwi K, Bellone S, Cocco E, Cargnelutti M, Casagrande F, Bellone M, Abu-Khalaf M, Buza N, Tavassoli FA, Hui P, Silasi DA, Azodi M, Schwartz PE, Rutherford TJ, Pecorelli S, Santin AD. In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma. Br J Cancer. 2010;102:134–43.PubMedGoogle Scholar
  133. 133.
    Bellone S, Roque D, Cocco E, Gasparrini S, Bortolomai I, Buza N, Abu-Khalaf M, Silasi DA, Ratner E, Azodi M, Schwartz PE, Rutherford TJ, Pecorelli S, Santin AD. Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy. Br J Cancer. 2012;106:1543–50.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Kamat AA, Merritt WM, Coffey D, Lin YG, Patel PR, Broaddus R, Nugent E, Han LY, Landen Jr CN, Spannuth WA, Lu C, Coleman RL, Gershenson DM, Sood AK. Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res. 2007;13:7487–95.PubMedGoogle Scholar
  135. 135.
    Patel RR, Sengupta S, Kim HR, Klein-Szanto AJ, Pyle JR, Zhu F, Li T, Ross EA, Oseni S, Fargnoli J, Jordan VC. Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors. Eur J Cancer. 2010;46:1537–53.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Zhang X, Kyo S, Nakamura M, Mizumoto Y, Maida Y, Bono Y, Takakura M, Fujiwara H. Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells. Cancer Lett. 2014;345:106–14.PubMedGoogle Scholar
  137. 137.
    Bilir A, Erguven M, Ermis E, Sencan M, Yazihan N. Combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinoma in vitro. J Gynecol Oncol. 2011;22:225–32.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Khalifa MA, Abdoh AA, Mannel RS, Haraway SD, Walker JL, Min KW. Prognostic utility of epidermal growth factor receptor overexpression in endometrial adenocarcinoma. Cancer. 1994;73:370–6.PubMedGoogle Scholar
  139. 139.
    Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L, Maxwell GL, Fowler JM. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Oncol. 2006;24:2376–85.PubMedGoogle Scholar
  140. 140.
    Shang C, Lu YM, Meng LR. MicroRNA-125b down-regulation mediates endometrial cancer invasion by targeting ERBB2. Med Sci Monit. 2012;18:BR149–55.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Zhao FJ, Zhang SL, Ma L, Gao H, Zhong ZH. Efficacy of c-erbB-2 antisense oligonucleotide transfection on uterine endometrial cancer HEC-1A cell lines. Eur J Gynaecol Oncol. 2007;28:263–9.PubMedGoogle Scholar
  142. 142.
    Zhao FJ, Zhang SL, Ma L, Gao H, Zong ZH. Inhibitory effects of c-erbB-2 antisense oligonucleotide transfection on uterine endometrial cancer Ishikawa cell lines. Eur J Gynaecol Oncol. 2009;30:54–9.PubMedGoogle Scholar
  143. 143.
    Biscuola M, VAN DE Vijver K, Castilla MA, Romero-Perez L, Lopez-Garcia MA, Diaz-Martin J, Matias-Guiu X, Oliva E, Palacios Calvo J. Oncogene alterations in endometrial carcinosarcomas. Hum Pathol. 2013;44:852–9.PubMedGoogle Scholar
  144. 144.
    Saghir FS, Rose IM, Dali AZ, Shamsuddin Z, Jamal AR, Mokhtar NM. Gene expression profiling and cancer-related pathways in type I endometrial carcinoma. Int J Gynecol Cancer. 2010;20:724–31.PubMedGoogle Scholar
  145. 145.
    Srinivasan R, Benton E, McCormick F, Thomas H, Gullick WJ. Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer. Clin Cancer Res. 1999;5:2877–83.PubMedGoogle Scholar
  146. 146.
    Ejskjaer K, Sorensen BS, Poulsen SS, Forman A, Nexo E, Mogensen O. Expression of the epidermal growth factor system in endometrioid endometrial cancer. Gynecol Oncol. 2007;104:158–67.PubMedGoogle Scholar
  147. 147.
    Liang H, Cheung LW, Li J, Ju Z, Yu S, Stemke-Hale K, Dogruluk T, Lu Y, Liu X, Gu C, Guo W, Scherer SE, Carter H, Westin SN, Dyer MD, Verhaak RG, Zhang F, Karchin R, Liu CG, Lu KH, Broaddus RR, Scott KL, Hennessy BT, Mills GB. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. Genome Res. 2012;22:2120–9.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Fleming GF, Sill MW, Darcy KM, Mcmeekin DS, Thigpen JT, Adler LM, Berek JS, Chapman JA, Disilvestro PA, Horowitz IR, Fiorica JV. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116:15–20.PubMedGoogle Scholar
  149. 149.
    Leslie KK, Sill MW, Fischer E, Darcy KM, Mannel RS, Tewari KS, Hanjani P, Wilken JA, Baron AT, Godwin AK, Schilder RJ, Singh M, Maihle NJ. A phase II evaluation of gefitinib in the treatment of persistent or recurrent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129:486–94.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Nogami Y, Banno K, Kisu I, Yanokura M, Umene K, Masuda K, Kobayashi Y, Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D. Current status of molecular-targeted drugs for endometrial cancer (Review). Mol Clin Oncol. 2013;1:799–804.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Oza AM, Eisenhauer EA, Elit L, Cutz JC, Sakurada A, Tsao MS, Hoskins PJ, Biagi J, Ghatage P, Mazurka J, Provencher D, Dore N, Dancey J, Fyles A. Phase II study of erlotinib in recurrent or metastatic endometrial cancer: NCIC IND-148. J Clin Oncol. 2008;26:4319–25.PubMedGoogle Scholar
  152. 152.
    Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, Gotlieb WH, Hoskins PJ, Ghatage P, Tonkin KS, MacKay HJ, Mazurka J, Sederias J, Ivy P, Dancey JE, Eisenhauer EA. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29:3278–85.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Colombo N, Mcmeekin DS, Schwartz PE, Sessa C, Gehrig PA, Holloway R, Braly P, Matei D, Morosky A, Dodion PF, Einstein MH, Haluska F. Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer. 2013;108:1021–6.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Ray-Coquard I, Favier L, Weber B, Roemer-Becuwe C, Bougnoux P, Fabbro M, Floquet A, Joly F, Plantade A, Paraiso D, Pujade-Lauraine E. Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO. Br J Cancer. 2013;108:1771–7.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Leslie KK, Sill MW, Lankes HA, Fischer EG, Godwin AK, Gray H, Schilder RJ, Walker JL, Tewari K, Hanjani P, Abulafia O, Rose PG. Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer. Gynecol Oncol. 2012;127:345–50.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Aghajanian C, Sill MW, Darcy KM, Greer B, Mcmeekin DS, Rose PG, Rotmensch J, Barnes MN, Hanjani P, Leslie KK. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29:2259–65.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Powell MA, Sill MW, Goodfellow PJ, Benbrook DM, Lankes HA, Leslie KK, Jeske Y, Mannel RS, Spillman MA, Lee PS, Hoffman JS, Mcmeekin DS, Pollock PM. A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol. 2014;135:38–43.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Nimeiri HS, Oza AM, Morgan RJ, Huo D, Elit L, Knost JA, Wade JL, Agamah E, Vokes EE, Fleming GF. A phase II study of sorafenib in advanced uterine carcinoma/carcinosarcoma: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 2010;117:37–40.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Castonguay V, Lheureux S, Welch S, MacKay HJ, Hirte H, Fleming G, Morgan R, Wang L, Blattler C, Ivy PS, Oza AM. A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: a study of the Princess Margaret, Chicago and California Consortia. Gynecol Oncol. 2014;134:274–80.PubMedGoogle Scholar
  160. 160.
    Alvarez EA, Brady WE, Walker JL, Rotmensch J, Zhou XC, Kendrick JE, Yamada SD, Schilder JM, Cohn DE, Harrison CR, Moore KN, Aghajanian C. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129:22–7.PubMedGoogle Scholar
  161. 161.
    Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M, Levenback C, Zhang Q, Ring K, Munsell MF, Gershenson DM, Lu KH, Coleman RL. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2015. doi: 10.1200/JCO.2014.58.3401.PubMedCentralGoogle Scholar
  162. 162.
    Schlaeppi JM, Wood JM. Targeting vascular endothelial growth factor (VEGF) for anti-tumor therapy, by anti-VEGF neutralizing monoclonal antibodies or by VEGF receptor tyrosine-kinase inhibitors. Cancer Metastasis Rev. 1999;18:473–81.PubMedGoogle Scholar
  163. 163.
    Fine BA, Valente PT, Feinstein GI, Dey T. VEGF, flt-1, and KDR/flk-1 as prognostic indicators in endometrial carcinoma. Gynecol Oncol. 2000;76:33–9.PubMedGoogle Scholar
  164. 164.
    Talvensaari-Mattila A, Soini Y, Santala M. VEGF and its receptors (flt-1 and KDR/flk-1) as prognostic indicators in endometrial carcinoma. Tumour Biol. 2005;26:81–7.PubMedGoogle Scholar
  165. 165.
    Wang J, Taylor A, Showeil R, Trivedi P, Horimoto Y, Bagwan I, Ewington L, Lam EW, El-Bahrawy MA. Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma. Cytokine. 2014;68:94–100.PubMedGoogle Scholar
  166. 166.
    Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, Emoto M, Sakamoto A, Sakamoto T, Maruyama H, Sato S, Mizunuma H, Smith SK. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res. 2003;9:1361–9.PubMedGoogle Scholar
  167. 167.
    Hoch RV, Soriano P. Roles of PDGF in animal development. Development. 2003;130:4769–84.PubMedGoogle Scholar
  168. 168.
    Matsumoto H, Nasu K, Nishida M, Ito H, Bing S, Miyakawa I. Regulation of proliferation, motility, and contractility of human endometrial stromal cells by platelet-derived growth factor. J Clin Endocrinol Metab. 2005;90:3560–7.PubMedGoogle Scholar
  169. 169.
    Munson L, Upadhyaya NB, VAN Meter S. Platelet-derived growth factor promotes endometrial epithelial cell proliferation. Am J Obstet Gynecol. 1995;173:1820–5.PubMedGoogle Scholar
  170. 170.
    Wang Y, Qiu H, Hu W, Li S, Yu J. Over-expression of platelet-derived growth factor-D promotes tumor growth and invasion in endometrial cancer. Int J Mol Sci. 2014;15:4780–94.PubMedPubMedCentralGoogle Scholar
  171. 171.
    Slomovitz BM, Broaddus RR, Schmandt R, Wu W, Oh JC, Ramondetta LM, Burke TW, Gershenson DM, Lu KH. Expression of imatinib mesylate-targeted kinases in endometrial carcinoma. Gynecol Oncol. 2004;95:32–6.PubMedGoogle Scholar
  172. 172.
    Adams SF, Hickson JA, Hutto JY, Montag AG, Lengyel E, Yamada SD. PDGFR-alpha as a potential therapeutic target in uterine sarcomas. Gynecol Oncol. 2007;104:524–8.PubMedGoogle Scholar
  173. 173.
    Cossu-Rocca P, Contini M, Uras MG, Muroni MR, Pili F, Carru C, Bosincu L, Massarelli G, Nogales FF, DE Miglio MR. Tyrosine kinase receptor status in endometrial stromal sarcoma: an immunohistochemical and genetic-molecular analysis. Int J Gynecol Pathol. 2012;31:570–9.PubMedGoogle Scholar
  174. 174.
    Liegl B, Gully C, Reich O, Nogales FF, Beham A, Regauer S. Expression of platelet-derived growth factor receptor in low-grade endometrial stromal sarcomas in the absence of activating mutations. Histopathology. 2007;50:448–52.PubMedGoogle Scholar
  175. 175.
    Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, Wellner D, Leder P, Besmer P. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell. 1990;63:225–33.PubMedGoogle Scholar
  176. 176.
    Williams DE, Eisenman J, Baird A, Rauch C, VAN Ness K, March CJ, Park LS, Martin U, Mochizuki DY, Boswell HS, et al. Identification of a ligand for the c-kit proto-oncogene. Cell. 1990;63:167–74.PubMedGoogle Scholar
  177. 177.
    Hines SJ, Organ C, Kornstein MJ, Krystal GW. Coexpression of the c-kit and stem cell factor genes in breast carcinomas. Cell Growth Differ. 1995;6:769–79.PubMedGoogle Scholar
  178. 178.
    Krystal GW, Honsawek S, Litz J, Buchdunger E. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res. 2000;6:3319–26.PubMedGoogle Scholar
  179. 179.
    Elmore LW, Domson K, Moore JR, Kornstein M, Burks RT. Expression of c-kit (CD117) in benign and malignant human endometrial epithelium. Arch Pathol Lab Med. 2001;125:146–51.PubMedGoogle Scholar
  180. 180.
    Scobie JV, Acs G, Bandera CA, Blank SV, Wheeler JE, Pasha TL, Salscheider M, Zhang PJ. C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathologic significance. Int J Gynecol Pathol. 2003;22:149–55.PubMedGoogle Scholar
  181. 181.
    Arceci RJ, Shanahan F, Stanley ER, Pollard JW. Temporal expression and location of colony-stimulating factor 1 (CSF-1) and its receptor in the female reproductive tract are consistent with CSF-1-regulated placental development. Proc Natl Acad Sci U S A. 1989;86:8818–22.PubMedPubMedCentralGoogle Scholar
  182. 182.
    Bartocci A, Pollard JW, Stanley ER. Regulation of colony-stimulating factor 1 during pregnancy. J Exp Med. 1986;164:956–61.PubMedGoogle Scholar
  183. 183.
    Daiter E, Pampfer S, Yeung YG, Barad D, Stanley ER, Pollard JW. Expression of colony-stimulating factor-1 in the human uterus and placenta. J Clin Endocrinol Metab. 1992;74:850–8.PubMedGoogle Scholar
  184. 184.
    Kauma SW, Aukerman SL, Eierman D, Turner T. Colony-stimulating factor-1 and c-fms expression in human endometrial tissues and placenta during the menstrual cycle and early pregnancy. J Clin Endocrinol Metab. 1991;73:746–51.PubMedGoogle Scholar
  185. 185.
    Pampfer S, Daiter E, Barad D, Pollard JW. Expression of the colony-stimulating factor-1 receptor (c-fms proto-oncogene product) in the human uterus and placenta. Biol Reprod. 1992;46:48–57.PubMedGoogle Scholar
  186. 186.
    Pollard JW, Bartocci A, Arceci R, Orlofsky A, Ladner MB, Stanley ER. Apparent role of the macrophage growth factor, CSF-1, in placental development. Nature. 1987;330:484–6.PubMedGoogle Scholar
  187. 187.
    Baiocchi G, Kavanagh JJ, Talpaz M, Wharton JT, Gutterman JU, Kurzrock R. Expression of the macrophage colony-stimulating factor and its receptor in gynecologic malignancies. Cancer. 1991;67:990–6.PubMedGoogle Scholar
  188. 188.
    Kacinski BM, Chambers SK, Stanley ER, Carter D, Tseng P, Scata KA, Chang DH, Pirro MH, Nguyen JT, Ariza A, et al. The cytokine CSF-1 (M-CSF) expressed by endometrial carcinomas in vivo and in vitro, may also be a circulating tumor marker of neoplastic disease activity in endometrial carcinoma patients. Int J Radiat Oncol Biol Phys. 1990;19:619–26.PubMedGoogle Scholar
  189. 189.
    Leiserowitz GS, Harris SA, Subramaniam M, Keeney GL, Podratz KC, Spelsberg TC. The proto-oncogene c-fms is overexpressed in endometrial cancer. Gynecol Oncol. 1993;49:190–6.PubMedGoogle Scholar
  190. 190.
    Smith HO, Anderson PS, Kuo DY, Goldberg GL, Devictoria CL, Boocock CA, Jones JG, Runowicz CD, Stanley ER, Pollard JW. The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma. Clin Cancer Res. 1995;1:313–25.PubMedGoogle Scholar
  191. 191.
    Anderson PS, Smith HO, Goldberg GL, Fields AL, Runowicz CD, Pollard JW. Colony-stimulating factor-1 and its receptor do not have a role in the pathogenesis of uterine sarcomas. Gynecol Oncol. 1999;74:202–7.PubMedGoogle Scholar
  192. 192.
    Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999;19:3278–88.PubMedPubMedCentralGoogle Scholar
  193. 193.
    Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R, Pezzino V, Belfiore A. A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab. 2002;87:245–54.PubMedGoogle Scholar
  194. 194.
    Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev. 2009;30:586–623.PubMedGoogle Scholar
  195. 195.
    Wang CF, Zhang G, Zhao LJ, Qi WJ, Li XP, Wang JL, Wei LH. Overexpression of the insulin receptor isoform A promotes endometrial carcinoma cell growth. PLoS One. 2013;8, e69001.PubMedPubMedCentralGoogle Scholar
  196. 196.
    Wang Y, Hua S, Tian W, Zhang L, Zhao J, Zhang H, Zhang W, Xue F. Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent. Gynecol Oncol. 2012;125:734–41.PubMedGoogle Scholar
  197. 197.
    Leroith D. Insulin-like growth factor I receptor signaling--overlapping or redundant pathways? Endocrinology. 2000;141:1287–8.PubMedGoogle Scholar
  198. 198.
    Kleinman D, Karas M, Roberts Jr CT, Leroith D, Phillip M, Segev Y, Levy J, Sharoni Y. Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol. Endocrinology. 1995;136:2531–7.PubMedGoogle Scholar
  199. 199.
    Rutanen EM. Insulin-like growth factors in endometrial function. Gynecol Endocrinol. 1998;12:399–406.PubMedGoogle Scholar
  200. 200.
    Tang XM, Rossi MJ, Masterson BJ, Chegini N. Insulin-like growth factor I (IGF-I), IGF-I receptors, and IGF binding proteins 1-4 in human uterine tissue: tissue localization and IGF-I action in endometrial stromal and myometrial smooth muscle cells in vitro. Biol Reprod. 1994;50:1113–25.PubMedGoogle Scholar
  201. 201.
    Zhu L, Pollard JW. Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc Natl Acad Sci U S A. 2007;104:15847–51.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Mccampbell AS, Broaddus RR, Loose DS, Davies PJ. Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res. 2006;12:6373–8.PubMedGoogle Scholar
  203. 203.
    Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–69.PubMedGoogle Scholar
  204. 204.
    Roy RN, Gerulath AH, Cecutti A, Bhavnani BR. Loss of IGF-II imprinting in endometrial tumors: overexpression in carcinosarcoma. Cancer Lett. 2000;153:67–73.PubMedGoogle Scholar
  205. 205.
    Peiro G, Lohse P, Mayr D, Diebold J. Insulin-like growth factor-I receptor and PTEN protein expression in endometrial carcinoma. Correlation with bax and bcl-2 expression, microsatellite instability status, and outcome. Am J Clin Pathol. 2003;120:78–85.PubMedGoogle Scholar
  206. 206.
    Attias-Geva Z, Bentov I, Ludwig DL, Fishman A, Bruchim I, Werner H. Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells. Eur J Cancer. 2011;47:1717–26.PubMedGoogle Scholar
  207. 207.
    Bitelman C, Sarfstein R, Sarig M, Attias-Geva Z, Fishman A, Werner H, Bruchim I. IGF1R-directed targeted therapy enhances the cytotoxic effect of chemotherapy in endometrial cancer. Cancer Lett. 2013;335:153–9.PubMedGoogle Scholar
  208. 208.
    Mendivil A, Zhou C, Cantrell LA, Gehrig PA, Malloy KM, Blok LJ, Burger CW, Bae-Jump VL. AMG 479, a novel IGF-1-R antibody, inhibits endometrial cancer cell proliferation through disruption of the PI3K/Akt and MAPK pathways. Reprod Sci. 2011;18:832–41.PubMedPubMedCentralGoogle Scholar
  209. 209.
    Shu S, Yang Y, Li X, Li T, Zhang Y, Xu C, Liang C, Wang X. Down-regulation of IGF-1R expression inhibits growth and enhances chemosensitivity of endometrial carcinoma in vitro. Mol Cell Biochem. 2011;353:225–33.PubMedGoogle Scholar
  210. 210.
    Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood. 2007;110:2259–67.PubMedPubMedCentralGoogle Scholar
  211. 211.
    Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.PubMedGoogle Scholar
  212. 212.
    Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8:11–23.PubMedGoogle Scholar
  213. 213.
    Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46:1773–80.PubMedPubMedCentralGoogle Scholar
  214. 214.
    Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, Ishikawa Y, Kimura H, Mitsudomi T, Tanio Y, Mano H. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734–9.PubMedGoogle Scholar
  215. 215.
    Katayama R, Khan TM, Benes C, Lifshits E, Ebi H, Rivera VM, Shakespeare WC, Iafrate AJ, Engelman JA, Shaw AT. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011;108:7535–40.PubMedPubMedCentralGoogle Scholar
  216. 216.
    Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, Lathan C, Marcoux JP, Du J, Okuda K, Capelletti M, Shimamura T, Ercan D, Stumpfova M, Xiao Y, Weremowicz S, Butaney M, Heon S, Wilner K, Christensen JG, Eck MJ, Wong KK, Lindeman N, Gray NS, Rodig SJ, Janne PA. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011;71:6051–60.PubMedPubMedCentralGoogle Scholar
  217. 217.
    DI Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res. 1995;55:1129–38.PubMedGoogle Scholar
  218. 218.
    Gentile A, Trusolino L, Comoglio PM. The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev. 2008;27:85–94.PubMedGoogle Scholar
  219. 219.
    Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N, Walther MM, Choyke P, Linehan WM, Zbar B. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol. 1999;155:517–26.PubMedPubMedCentralGoogle Scholar
  220. 220.
    Scarpino S, Stoppacciaro A, Colarossi C, Cancellario F, Marzullo A, Marchesi M, Biffoni M, Comoglio PM, Prat M, Ruco LP. Hepatocyte growth factor (HGF) stimulates tumour invasiveness in papillary carcinoma of the thyroid. J Pathol. 1999;189:570–5.PubMedGoogle Scholar
  221. 221.
    Weidner KM, Hartmann G, Naldini L, Comoglio PM, Sachs M, Fonatsch C, Rieder H, Birchmeier W. Molecular characteristics of HGF-SF and its role in cell motility and invasion. EXS. 1993;65:311–28.PubMedGoogle Scholar
  222. 222.
    Birchmeier C, Birchmeier W, Gherardi E, VANDE Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915–25.PubMedGoogle Scholar
  223. 223.
    Bishop EA, Lengyel ER, Yamada SD, Montag A, Temkin SM. The expression of hepatocyte growth factor (HGF) and c-Met in uterine serous carcinoma. Gynecol Oncol. 2011;121:218–23.PubMedGoogle Scholar
  224. 224.
    Wagatsuma S, Konno R, Sato S, Yajima A. Tumor angiogenesis, hepatocyte growth factor, and c-Met expression in endometrial carcinoma. Cancer. 1998;82:520–30.PubMedGoogle Scholar
  225. 225.
    Kanayama S, Yamada Y, Kawaguchi R, Tsuji Y, Haruta S, Kobayashi H. Hepatocyte growth factor induces anoikis resistance by up-regulation of cyclooxygenase-2 expression in uterine endometrial cancer cells. Oncol Rep. 2008;19:117–22.PubMedGoogle Scholar
  226. 226.
    Park YH, Ryu HS, Choi DS, Chang KH, Park DW, Min CK. Effects of hepatocyte growth factor on the expression of matrix metalloproteinases and their tissue inhibitors during the endometrial cancer invasion in a three-dimensional coculture. Int J Gynecol Cancer. 2003;13:53–60.PubMedGoogle Scholar
  227. 227.
    Yoshizawa Y, Yamada Y, Kanayama S, Shigetomi H, Kawaguchi R, Yoshida S, Nagai A, Furukawa N, Oi H, Kobayashi H. Signaling pathway involved in cyclooxygenase-2 up-regulation by hepatocyte growth factor in endometrial cancer cells. Oncol Rep. 2011;26:957–64.PubMedGoogle Scholar
  228. 228.
    Korc M, Friesel RE. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets. 2009;9:639–51.PubMedPubMedCentralGoogle Scholar
  229. 229.
    Ornitz DM, Xu J, Colvin JS, Mcewen DG, Macarthur CA, Coulier F, Gao G, Goldfarb M. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996;271:15292–7.PubMedGoogle Scholar
  230. 230.
    Ahmad I, Iwata T, Leung HY. Mechanisms of FGFR-mediated carcinogenesis. Biochim Biophys Acta. 2012;1823:850–60.PubMedGoogle Scholar
  231. 231.
    Presta M, Dell’era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005;16:159–78.PubMedGoogle Scholar
  232. 232.
    Gatius S, Velasco A, Azueta A, Santacana M, Pallares J, Valls J, Dolcet X, Prat J, Matias-Guiu X. FGFR2 alterations in endometrial carcinoma. Mod Pathol. 2011;24:1500–10.PubMedGoogle Scholar
  233. 233.
    Moller B, Rasmussen C, Lindblom B, Olovsson M. Expression of the angiogenic growth factors VEGF, FGF-2, EGF and their receptors in normal human endometrium during the menstrual cycle. Mol Hum Reprod. 2001;7:65–72.PubMedGoogle Scholar
  234. 234.
    Tsai SJ, Wu MH, Chen HM, Chuang PC, Wing LY. Fibroblast growth factor-9 is an endometrial stromal growth factor. Endocrinology. 2002;143:2715–21.PubMedGoogle Scholar
  235. 235.
    Wollenhaupt K, Welter H, Brussow KP, Einspanier R. Regulation of endometrial fibroblast growth factor 7 (FGF-7) and its receptor FGFR2IIIb in gilts after sex steroid replacements, and during the estrous cycle and early gestation. J Reprod Dev. 2005;51:509–19.PubMedGoogle Scholar
  236. 236.
    Wollenhaupt K, Welter H, Einspanier R, Manabe N, Brussow KP. Expression of epidermal growth factor receptor (EGF-R), vascular endothelial growth factor receptor (VEGF-R) and fibroblast growth factor receptor (FGF-R) systems in porcine oviduct and endometrium during the time of implantation. J Reprod Dev. 2004;50:269–78.PubMedGoogle Scholar
  237. 237.
    Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC, Hatton C, Nicoletti R, Winckler W, Grewal R, Hanna M, Wyhs N, Ziaugra L, Richter DJ, Trovik J, Engelsen IB, Stefansson IM, Fennell T, Cibulskis K, Zody MC, Akslen LA, Gabriel S, Wong KK, Sellers WR, Meyerson M, Greulich H. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A. 2008;105:8713–7.PubMedPubMedCentralGoogle Scholar
  238. 238.
    Pollock PM, Gartside MG, Dejeza LC, Powell MA, Mallon MA, Davies H, Mohammadi M, Futreal PA, Stratton MR, Trent JM, Goodfellow PJ. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene. 2007;26:7158–62.PubMedPubMedCentralGoogle Scholar
  239. 239.
    Ibrahimi OA, Eliseenkova AV, Plotnikov AN, Yu K, Ornitz DM, Mohammadi M. Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc Natl Acad Sci U S A. 2001;98:7182–7.PubMedPubMedCentralGoogle Scholar
  240. 240.
    Ibrahimi OA, Zhang F, Eliseenkova AV, Itoh N, Linhardt RJ, Mohammadi M. Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities. Hum Mol Genet. 2004;13:2313–24.PubMedPubMedCentralGoogle Scholar
  241. 241.
    Yu K, Herr AB, Waksman G, Ornitz DM. Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. Proc Natl Acad Sci U S A. 2000;97:14536–41.PubMedPubMedCentralGoogle Scholar
  242. 242.
    Byron SA, Gartside MG, Wellens CL, Mallon MA, Keenan JB, Powell MA, Goodfellow PJ, Pollock PM. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 2008;68:6902–7.PubMedGoogle Scholar
  243. 243.
    Foo SS, Turner CJ, Adams S, Compagni A, Aubyn D, Kogata N, Lindblom P, Shani M, Zicha D, Adams RH. Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell. 2006;124:161–73.PubMedGoogle Scholar
  244. 244.
    Iwamasa H, Ohta K, Yamada T, Ushijima K, Terasaki H, Tanaka H. Expression of Eph receptor tyrosine kinases and their ligands in chick embryonic motor neurons and hindlimb muscles. Dev Growth Differ. 1999;41:685–98.PubMedGoogle Scholar
  245. 245.
    Kilpatrick TJ, Brown A, Lai C, Gassmann M, Goulding M, Lemke G. Expression of the Tyro4/Mek4/Cek4 gene specifically marks a subset of embryonic motor neurons and their muscle targets. Mol Cell Neurosci. 1996;7:62–74.PubMedGoogle Scholar
  246. 246.
    Abal M, Planaguma J, Gil-Moreno A, Monge M, Gonzalez M, Baro T, Garcia A, Castellvi J, Ramon Y Cajal S, Xercavins J, Alameda F, Reventos J. Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors. Histol Histopathol. 2006;21:197–204.PubMedGoogle Scholar
  247. 247.
    Albright CD, Kaufman DG. Transforming growth factor-beta 1 mediates communication between human endometrial carcinoma cells and stromal cells. Pathobiology. 1995;63:314–9.PubMedGoogle Scholar
  248. 248.
    Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14:130–46.PubMedPubMedCentralGoogle Scholar
  249. 249.
    Attisano L, Wrana JL. Smads as transcriptional co-modulators. Curr Opin Cell Biol. 2000;12:235–43.PubMedGoogle Scholar
  250. 250.
    Bao R, Christova T, Song S, Angers S, Yan X, Attisano L. Inhibition of tankyrases induces Axin stabilization and blocks Wnt signalling in breast cancer cells. PLoS One. 2012;7:e48670.PubMedPubMedCentralGoogle Scholar
  251. 251.
    Barford D. Structural insights into anaphase-promoting complex function and mechanism. Philos Trans R Soc Lond B Biol Sci. 2011;366:3605–24.PubMedPubMedCentralGoogle Scholar
  252. 252.
    Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.PubMedGoogle Scholar
  253. 253.
    Beck H, Nähse V, Larsen MS, Groth P, Clancy T, Lees M, Jørgensen M, Helleday T, Syljuåsen RG, Sørensen CS. Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase. J Cell Biol. 2010;188:629–38.PubMedPubMedCentralGoogle Scholar
  254. 254.
    Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem. 2002;71:333–74.PubMedGoogle Scholar
  255. 255.
    Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6:506–20.PubMedGoogle Scholar
  256. 256.
    Bing L, Hong C, Li-Xin S, Wei G. MicroRNA-543 suppresses endometrial cancer oncogenicity via targeting FAK and TWIST1 expression. Arch Gynecol Obstet. 2014;290:533–41.PubMedGoogle Scholar
  257. 257.
    Chan DW, Mak CS, Leung TH, Chan KK, Ngan HY. Down-regulation of Sox7 is associated with aberrant activation of Wnt/b-catenin signaling in endometrial cancer. Oncotarget. 2012;3:1546–56.PubMedPubMedCentralGoogle Scholar
  258. 258.
    Chandra V, Fatima I, Manohar M, Popli P, Sirohi VK, Hussain MK, Hajela K, Sankhwar P, Dwivedi A. Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway. Cell Death Dis. 2014;5:e1380.PubMedPubMedCentralGoogle Scholar
  259. 259.
    Chatzizacharias NA, Giaginis C, Gatzidou E, Tsourouflis G, Sfiniadakis I, Alexandrou P, Theocharis SE. Expression and clinical significance of FAK and Src proteins in human endometrial adenocarcinoma. Pathol Oncol Res. 2011;17:277–85.PubMedGoogle Scholar
  260. 260.
    Chen CR, Kang Y, Siegel PM, Massagué J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell. 2002;110:19–32.PubMedGoogle Scholar
  261. 261.
    Cicenas J, Kalyan K, Sorokinas A, Jatulyte A, Valiunas D, Kaupinis A, Valius M. Highlights of the latest advances in research on CDK inhibitors. Cancers (Basel). 2014;6:2224–42.Google Scholar
  262. 262.
    Clark EA, Brugge JS. Integrins and signal transduction pathways: the road taken. Science. 1995;268:233–9.PubMedGoogle Scholar
  263. 263.
    Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192–205.PubMedGoogle Scholar
  264. 264.
    Cobrinik D. Pocket proteins and cell cycle control. Oncogene. 2005;24:2796–809.PubMedGoogle Scholar
  265. 265.
    Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene. 1999;18:2883–91.PubMedGoogle Scholar
  266. 266.
    Czernilofsky AP, Levinson AD, Varmus HE, Bishop JM, Tischer E, Goodman HM. Nucleotide sequence of an avian sarcoma virus oncogene (src) and proposed amino acid sequence for gene product. Nature. 1980;287:198–203.PubMedGoogle Scholar
  267. 267.
    DE Larco JE, Todaro GJ. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A. 1978;75:4001–5.PubMedPubMedCentralGoogle Scholar
  268. 268.
    Dellinger TH, Planutis K, Jandial DD, Eskander RN, Martinez ME, Zi X, Monk BJ, Holcombe RF. Expression of the Wnt antagonist Dickkopf-3 is associated with prognostic clinicopathologic characteristics and impairs proliferation and invasion in endometrial cancer. Gynecol Oncol. 2012;126:259–67.PubMedPubMedCentralGoogle Scholar
  269. 269.
    Dellinger TH, Planutis K, Tewari KS, Holcombe RF. Role of canonical Wnt signaling in endometrial carcinogenesis. Expert Rev Anticancer Ther. 2012;12:51–62.PubMedGoogle Scholar
  270. 270.
    Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985;316:701–5.PubMedGoogle Scholar
  271. 271.
    Desouki MM, Rowan BG. SRC kinase and mitogen-activated protein kinases in the progression from normal to malignant endometrium. Clin Cancer Res. 2004;10:546–55.PubMedGoogle Scholar
  272. 272.
    Diallo A, Prigent C. The serine/threonine kinases that control cell cycle progression as therapeutic targets. Bull Cancer. 2011;98:1335–45.PubMedGoogle Scholar
  273. 273.
    Dowdy SC, Mariani A, Reinholz MM, Keeney GL, Spelsberg TC, Podratz KC, Janknecht R. Overexpression of the TGF-beta antagonist Smad7 in endometrial cancer. Gynecol Oncol. 2005;96:368–73.PubMedGoogle Scholar
  274. 274.
    Dravid G, Ye Z, Hammond H, Chen G, Pyle A, Donovan P, Yu X, Cheng L. Defining the role of Wnt/beta-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells. 2005;23:1489–501.PubMedGoogle Scholar
  275. 275.
    Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF. Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb. Proc Natl Acad Sci U S A. 1997;94:10699–704.PubMedPubMedCentralGoogle Scholar
  276. 276.
    Felix AS, Sherman ME, Hewitt SM, Gunja MZ, Yang HP, Cora RL, Boudreau V, Ylaya K, Lissowska J, Brinton LA, Wentzensen N. Cell-cycle protein expression in a population-based study of ovarian and endometrial cancers. Front Oncol. 2015;5:25.PubMedPubMedCentralGoogle Scholar
  277. 277.
    Fernandez-Hernandez R, Rafel M, Fuste NP, Aguayo RS, Casanova JM, Egea J, Ferrezuelo F, Gari E. Cyclin D1 localizes in the cytoplasm of keratinocytes during skin differentiation and regulates cell-matrix adhesion. Cell Cycle. 2013;12:2510–7.PubMedPubMedCentralGoogle Scholar
  278. 278.
    Finn RS. Targeting Src in breast cancer. Ann Oncol. 2008;19:1379–86.PubMedGoogle Scholar
  279. 279.
    Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene. 1990;5:1329–36.PubMedGoogle Scholar
  280. 280.
    Florio P, Ciarmela P, Reis FM, Toti P, Galleri L, Santopietro R, Tiso E, Tosi P, Petraglia F. Inhibin alpha-subunit and the inhibin coreceptor betaglycan are downregulated in endometrial carcinoma. Eur J Endocrinol. 2005;152:277–84.PubMedGoogle Scholar
  281. 281.
    Frame MC. Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta. 2002;1602:114–30.PubMedGoogle Scholar
  282. 282.
    Gabriel B, Hasenburg A, Waizenegger M, Orlowska-Volk M, Stickeler E, Zur Hausen A. Expression of focal adhesion kinase in patients with endometrial cancer: a clinicopathologic study. Int J Gynecol Cancer. 2009;19:1221–5.PubMedGoogle Scholar
  283. 283.
    Gandhirajan RK, Staib PA, Minke K, Gehrke I, Plickert G, Schlösser A, Schmitt EK, Hallek M, Kreuzer KA. Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Neoplasia. 2010;12:326–35.PubMedPubMedCentralGoogle Scholar
  284. 284.
    Gao Y, Li S, Li Q. Uterine epithelial cell proliferation and endometrial hyperplasia: evidence from a mouse model. Mol Hum Reprod. 2014;20:776–86.PubMedPubMedCentralGoogle Scholar
  285. 285.
    Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, Cibulskis K, Saksena G, Lawrence MS, Qian ZR, Nishihara R, Van Allen EM, Hahn WC, Gabriel SB, Lander ES, Getz G, Ogino S, Fuchs CS, Garraway LA. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet. 2014;46:1264–6.PubMedPubMedCentralGoogle Scholar
  286. 286.
    Gold LI, Saxena B, Mittal KR, Marmor M, Goswami S, Nactigal L, Korc M, Demopoulos RI. Increased expression of transforming growth factor beta isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium: evidence for paracrine and autocrine action. Cancer Res. 1994;54:2347–58.PubMedGoogle Scholar
  287. 287.
    Gumbiner BM. Signal transduction of beta-catenin. Curr Opin Cell Biol. 1995;7:634–40.PubMedGoogle Scholar
  288. 288.
    Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, Fischer M, Chaudhari A, Ji M, Kapoun AM, Lam A, Lazetic S, Ma S, Mitra S, Park IK, Pickell K, Sato A, Satyal S, Stroud M, Tran H, Yen WC, Lewicki J, Hoey T. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A. 2012;109:11717–22.PubMedPubMedCentralGoogle Scholar
  289. 289.
    Gurniak CB, Berg LJ. Murine JAK3 is preferentially expressed in hematopoietic tissues and lymphocyte precursor cells. Blood. 1996;87:3151–60.PubMedGoogle Scholar
  290. 290.
    Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998;12:186–97.PubMedPubMedCentralGoogle Scholar
  291. 291.
    Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, Falb D. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89:1165–73.PubMedGoogle Scholar
  292. 292.
    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, DA Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–12.PubMedGoogle Scholar
  293. 293.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49–53.PubMedGoogle Scholar
  294. 294.
    Kamat AA, Coffey D, Merritt WM, Nugent E, Urbauer D, Lin YG, Edwards C, Broaddus R, Coleman RL, Sood AK. EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer. Cancer. 2009;115:2684–92.PubMedPubMedCentralGoogle Scholar
  295. 295.
    Kanaya T, Kyo S, Maida Y, Yatabe N, Tanaka M, Nakamura M, Inoue M. Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. Oncogene. 2003;22:2352–60.PubMedGoogle Scholar
  296. 296.
    Kishimoto T. Entry into mitosis: a solution to the decades-long enigma of MPF. Chromosoma. 2015;124(4):417–28.PubMedPubMedCentralGoogle Scholar
  297. 297.
    Kobayashi K, Sagae S, Nishioka Y, Tokino T, Kudo R. Mutations of the beta-catenin gene in endometrial carcinomas. Jpn J Cancer Res. 1999;90:55–9.PubMedGoogle Scholar
  298. 298.
    Kohn AD, Moon RT. Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium. 2005;38:439–46.PubMedGoogle Scholar
  299. 299.
    Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.PubMedGoogle Scholar
  300. 300.
    Kuhn E, Wu RC, Guan B, Wu G, Zhang J, Wang Y, Song L, Yuan X, Wei L, Roden RB, Kuo KT, Nakayama K, Clarke B, Shaw P, Olvera N, Kurman RJ, Levine DA, Wang TL, Shih IM. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Cancer Inst. 2012;104:1503–13.PubMedPubMedCentralGoogle Scholar
  301. 301.
    Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L. The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer. 2000;88:814–24.PubMedGoogle Scholar
  302. 302.
    Le PN, Mcdermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 2015;146C:1–11.Google Scholar
  303. 303.
    Lei X, Wang L, Yang J, Sun LZ. TGFbeta signaling supports survival and metastasis of endometrial cancer cells. Cancer Manag Res. 2009;2009:15–24.PubMedGoogle Scholar
  304. 304.
    Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci. 2014;105:1087–92.PubMedPubMedCentralGoogle Scholar
  305. 305.
    Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–97.PubMedGoogle Scholar
  306. 306.
    Lin HY, Wang XF, Ng-Eaton E, Weinberg RA, Lodish HF. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell. 1992;68:775–85.PubMedGoogle Scholar
  307. 307.
    Liu FS, Chen JT, Hsieh YT, Ho ES, Hung MJ, Lu CH, Chiou LC. Loss of Smad4 protein expression occurs infrequently in endometrial carcinomas. Int J Gynecol Pathol. 2003;22:347–52.PubMedGoogle Scholar
  308. 308.
    Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, Mcnamara P, Sellers WR, Petruzzelli L, Boral AL, Seidel HM, Mclaughlin ME, Che J, Carey TE, Vanasse G, Harris JL. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013;110:20224–9.PubMedPubMedCentralGoogle Scholar
  309. 309.
    Livasy CA, Moore D, Cance WG, Lininger RA. Focal adhesion kinase overexpression in endometrial neoplasia. Appl Immunohistochem Mol Morphol. 2004;12:342–5.PubMedGoogle Scholar
  310. 310.
    Luo KX, Zhu YF, Zhang LX, He HT, Wang XS, Zhang L. In situ investigation of Fas/FasL expression in chronic hepatitis B infection and related liver diseases. J Viral Hepat. 1997;4:303–7.PubMedGoogle Scholar
  311. 311.
    Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014;15:122.PubMedPubMedCentralGoogle Scholar
  312. 312.
    Martin GS. The hunting of the Src. Nat Rev Mol Cell Biol. 2001;2:467–75.PubMedGoogle Scholar
  313. 313.
    Massagué J. TGFbeta in Cancer. Cell. 2008;134:215–30.PubMedPubMedCentralGoogle Scholar
  314. 314.
    Massagué J. TGF-β signaling in development and disease. FEBS Lett. 2012;586:1833.PubMedGoogle Scholar
  315. 315.
    Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma. Histopathology. 2013;62:111–23.PubMedGoogle Scholar
  316. 316.
    Matsuzaki S, Darcha C. In vitro effects of a small-molecule antagonist of the Tcf/ß-catenin complex on endometrial and endometriotic cells of patients with endometriosis. PLoS One. 2013;8:e61690.PubMedPubMedCentralGoogle Scholar
  317. 317.
    Merritt WM, Kamat AA, Hwang JY, Bottsford-Miller J, Lu C, Lin YG, Coffey D, Spannuth WA, Nugent E, Han LY, Landen CN, Nick AM, Stone RL, Coffman K, Bruckheimer E, Broaddus RR, Gershenson DM, Coleman RL, Sood AK. Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer. Cancer Biol Ther. 2010;10:1306–14.PubMedPubMedCentralGoogle Scholar
  318. 318.
    Milde-Langosch K, Bamberger AM, Goemann C, Rössing E, Rieck G, Kelp B, Löning T. Expression of cell-cycle regulatory proteins in endometrial carcinomas: correlations with hormone receptor status and clinicopathologic parameters. J Cancer Res Clin Oncol. 2001;127:537–44.PubMedGoogle Scholar
  319. 319.
    Mitselou A, Ioachim E, Zagorianakou N, Kitsiou E, Vougiouklakis T, Agnantis NJ. Expression of the cell-cycle regulatory proteins (cyclins D1 and E) in endometrial carcinomas: correlations with hormone receptor status, proliferating indices, tumor suppressor gene products (p53, pRb), and clinicopathological parameters. Eur J Gynaecol Oncol. 2004;25:719–24.PubMedGoogle Scholar
  320. 320.
    Miyazaki T, Kato H, Nakajima M, Sohda M, Fukai Y, Masuda N, Manda R, Fukuchi M, Tsukada K, Kuwano H. FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer. 2003;89:140–5.PubMedPubMedCentralGoogle Scholar
  321. 321.
    Mologni L, Brussolo S, Ceccon M, Gambacorti-Passerini C. Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells. PLoS One. 2012;7:e51449.PubMedPubMedCentralGoogle Scholar
  322. 322.
    Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.PubMedGoogle Scholar
  323. 323.
    Moses HL, Branum EL, Proper JA, Robinson RA. Transforming growth factor production by chemically transformed cells. Cancer Res. 1981;41:2842–8.PubMedGoogle Scholar
  324. 324.
    Muinelo-Romay L, Colas E, Barbazan J, Alonso-Alconada L, Alonso-Nocelo M, Bouso M, Curiel T, Cueva J, Anido U, Forteza J, Gil-Moreno A, Reventos J, Lopez-Lopez R, Abal M. High-risk endometrial carcinoma profiling identifies TGF-β1 as a key factor in the initiation of tumor invasion. Mol Cancer Ther. 2011;10:1357–66.PubMedGoogle Scholar
  325. 325.
    Munger JS, Harpel JG, Gleizes PE, Mazzieri R, Nunes I, Rifkin DB. Latent transforming growth factor-beta: structural features and mechanisms of activation. Kidney Int. 1997;51:1376–82.PubMedGoogle Scholar
  326. 326.
    Nakashima R, Song H, Enomoto T, Murata Y, Mcclaid MR, Casto BC, Weghorst CM. Genetic alterations in the transforming growth factor receptor complex in sporadic endometrial carcinoma. Gene Expr. 1999;8:341–52.PubMedGoogle Scholar
  327. 327.
    Parekh TV, Gama P, Wen X, Demopoulos R, Munger JS, Carcangiu ML, Reiss M, Gold LI. Transforming growth factor beta signaling is disabled early in human endometrial carcinogenesis concomitant with loss of growth inhibition. Cancer Res. 2002;62:2778–90.PubMedGoogle Scholar
  328. 328.
    Partanen J, Makela TP, Alitalo R, Lehvaslaiho H, Alitalo K. Putative tyrosine kinases expressed in K-562 human leukemia cells. Proc Natl Acad Sci U S A. 1990;87:8913–7.PubMedPubMedCentralGoogle Scholar
  329. 329.
    Peifer M, Pai LM, Casey M. Phosphorylation of the Drosophila adherens junction protein Armadillo: roles for wingless signal and zeste-white 3 kinase. Dev Biol. 1994;166:543–56.PubMedGoogle Scholar
  330. 330.
    Perlino E, Loverro G, Maiorano E, Giannini T, Cazzolla A, Napoli A, Fiore MG, Ricco R, Marra E, Selvaggi L. Down-regulated expression of transforming growth factor beta 1 mRNA in endometrial carcinoma. Br J Cancer. 1998;77:1260–6.PubMedPubMedCentralGoogle Scholar
  331. 331.
    Piestrzeniewicz-Ulanska D, Brys M, Semczuk A, Jakowicki JA, Krajewska WM. Expression of TGF-beta type I and II receptors in normal and cancerous human endometrium. Cancer Lett. 2002;186:231–9.PubMedGoogle Scholar
  332. 332.
    Piestrzeniewicz-Ulanska D, Brys M, Semczuk A, Jakowicki JA, Krajewska WM. Expression and intracellular localization of Smad proteins in human endometrial cancer. Oncol Rep. 2003;10:1539–44.PubMedGoogle Scholar
  333. 333.
    Piestrzeniewicz-Ulanska D, Brys M, Semczuk A, Rechberger T, Jakowicki JA, Krajewska WM. TGF-beta signaling is disrupted in endometrioid-type endometrial carcinomas. Gynecol Oncol. 2004;95:173–80.PubMedGoogle Scholar
  334. 334.
    Ragni N, Ferrero S, Prefumo F, Muschiato B, Gorlero F, Gualco M, Fulcheri E. The association between p53 expression, stage and histological features in endometrial cancer. Eur J Obstet Gynecol Reprod Biol. 2005;123:111–6.PubMedGoogle Scholar
  335. 335.
    Ren Y, Zhang Y, Liu RZ, Fenstermacher DA, Wright KL, Teer JK, Wu J. JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations. Sci Rep. 2013;3:3042.PubMedPubMedCentralGoogle Scholar
  336. 336.
    Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50.PubMedGoogle Scholar
  337. 337.
    Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A. 1981;78:5339–43.PubMedPubMedCentralGoogle Scholar
  338. 338.
    Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF, Sporn MB. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A. 1985;82:119–23.PubMedPubMedCentralGoogle Scholar
  339. 339.
    Saad RS, Jasnosz KM, Tung MY, Silverman JF. Endoglin (CD105) expression in endometrial carcinoma. Int J Gynecol Pathol. 2003;22:248–53.PubMedGoogle Scholar
  340. 340.
    Salvesen HB, Das S, Akslen LA. Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. Clin Cancer Res. 2000;6:153–9.PubMedGoogle Scholar
  341. 341.
    Salvesen HB, Gulluoglu MG, Stefansson I, Akslen LA. Significance of CD 105 expression for tumour angiogenesis and prognosis in endometrial carcinomas. APMIS. 2003;111:1011–8.PubMedGoogle Scholar
  342. 342.
    Santala S, Talvensaari-Mattila A, Soini Y, Honkavuori-Toivola M, Santala M. High expression of cyclin A is associated with poor prognosis in endometrial endometrioid adenocarcinoma. Tumour Biol. 2014;35:5395–9.PubMedGoogle Scholar
  343. 343.
    Santala S, Talvensaari-Mattila A, Soini Y, Santala M. Prognostic value of cyclin B in endometrial endometrioid adenocarcinoma. Tumour Biol. 2015;36:953–7.PubMedGoogle Scholar
  344. 344.
    Schlaepfer DD, Hauck CR, Sieg DJ. Signaling through focal adhesion kinase. Prog Biophys Mol Biol. 1999;71:435–78.PubMedGoogle Scholar
  345. 345.
    Schlosshauer PW, Pirog EC, Levine RL, Ellenson LH. Mutational analysis of the CTNNB1 and APC genes in uterine endometrioid carcinoma. Mod Pathol. 2000;13:1066–71.PubMedGoogle Scholar
  346. 346.
    Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 2009;28:151–66.PubMedGoogle Scholar
  347. 347.
    Schmitz MJ, Hendricks DT, Farley J, Taylor RR, Geradts J, Rose GS, Birrer MJ. p27 and cyclin D1 abnormalities in uterine papillary serous carcinoma. Gynecol Oncol. 2000;77:439–45.PubMedGoogle Scholar
  348. 348.
    Semczuk A, Jakowicki JA. Alterations of pRb1-cyclin D1-cdk4/6-p16(INK4A) pathway in endometrial carcinogenesis. Cancer Lett. 2004;203:1–12.PubMedGoogle Scholar
  349. 349.
    Seyedin SM, Thompson AY, Bentz H, Rosen DM, Mcpherson JM, Conti A, Siegel NR, Galluppi GR, Piez KA. Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem. 1986;261:5693–5.PubMedGoogle Scholar
  350. 350.
    Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–12.PubMedGoogle Scholar
  351. 351.
    Shih HC, Shiozawa T, Kato K, Imai T, Miyamoto T, Uchikawa J, Nikaido T, Konishi I. Immunohistochemical expression of cyclins, cyclin-dependent kinases, tumor-suppressor gene products, Ki-67, and sex steroid receptors in endometrial carcinoma: positive staining for cyclin A as a poor prognostic indicator. Hum Pathol. 2003;34:471–8.PubMedGoogle Scholar
  352. 352.
    Siegel PM, Massague J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 2003;3:807–21.PubMedGoogle Scholar
  353. 353.
    Stephen LJ, Fawkes AL, Verhoeve A, Lemke G, Brown A. A critical role for the EphA3 receptor tyrosine kinase in heart development. Dev Biol. 2007;302:66–79.PubMedGoogle Scholar
  354. 354.
    Sánchez-Tilló E, DE Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A. β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc Natl Acad Sci U S A. 2011;108:19204–9.PubMedPubMedCentralGoogle Scholar
  355. 355.
    Takai N, Miyazaki T, Fujisawa K, Nasu K, Miyakawa I. Expression of receptor tyrosine kinase EphB4 and its ligand ephrin-B2 is associated with malignant potential in endometrial cancer. Oncol Rep. 2001;8:567–73.PubMedGoogle Scholar
  356. 356.
    Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.PubMedGoogle Scholar
  357. 357.
    Thamilselvan V, Basson MD. Pressure activates colon cancer cell adhesion by inside-out focal adhesion complex and actin cytoskeletal signaling. Gastroenterology. 2004;126:8–18.PubMedGoogle Scholar
  358. 358.
    Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997;13:513–609.PubMedGoogle Scholar
  359. 359.
    Tian XH, Hou WJ, Fang Y, Fan J, Tong H, Bai SL, Chen Q, Xu H, Li Y. XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res. 2013;32:100.PubMedPubMedCentralGoogle Scholar
  360. 360.
    To C, Farnsworth RH, Vail ME, Chheang C, Gargett CE, Murone C, Llerena C, Major AT, Scott AM, Janes PW, Lackmann M. Hypoxia-controlled EphA3 marks a human endometrium-derived multipotent mesenchymal stromal cell that supports vascular growth. PLoS One. 2014;9:e112106.PubMedPubMedCentralGoogle Scholar
  361. 361.
    Toda T, Oku H, Khaskhely NM, Moromizato H, Ono I, Murata T. Analysis of microsatellite instability and loss of heterozygosity in uterine endometrial adenocarcinoma. Cancer Genet Cytogenet. 2001;126:120–7.PubMedGoogle Scholar
  362. 362.
    Tsai CL, Wu HM, Lin CY, Lin YJ, Chao A, Wang TH, Hsueh S, Lai CH, Wang HS. Estradiol and tamoxifen induce cell migration through GPR30 and activation of focal adhesion kinase (FAK) in endometrial cancers with low or without nuclear estrogen receptor alpha (ERalpha). PLoS One. 2013;8:e72999.PubMedPubMedCentralGoogle Scholar
  363. 363.
    Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell. 1998;95:779–91.PubMedGoogle Scholar
  364. 364.
    Umene K, Yanokura M, Banno K, Irie H, Adachi M, Iida M, Nakamura K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E, Aoki D. Aurora kinase A has a significant role as a therapeutic target and clinical biomarker in endometrial cancer. Int J Oncol. 2015;46:1498–506.PubMedPubMedCentralGoogle Scholar
  365. 365.
    Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol. 2008;19:385–93.PubMedGoogle Scholar
  366. 366.
    VAN NIMWEGEN MJ, VERKOEIJEN S, VAN BUREN L, BURG D, VAN DE WATER B. Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation. Cancer Res. 2005;65:4698–706.PubMedGoogle Scholar
  367. 367.
    VAN Themsche C, Mathieu I, Parent S, Asselin E. Transforming growth factor-beta3 increases the invasiveness of endometrial carcinoma cells through phosphatidylinositol 3-kinase-dependent up-regulation of X-linked inhibitor of apoptosis and protein kinase c-dependent induction of matrix metalloproteinase-9. J Biol Chem. 2007;282:4794–802.PubMedGoogle Scholar
  368. 368.
    Waaler J, Machon O, Tumova L, Dinh H, Korinek V, Wilson SR, Paulsen JE, Pedersen NM, Eide TJ, Machonova O, Gradl D, Voronkov A, VON Kries JP, Krauss S. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 2012;72:2822–32.PubMedGoogle Scholar
  369. 369.
    Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Luthi U, Barberis A, Benjamin LE, Makinen T, Nobes CD, Adams RH. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature. 2010;465:483–6.PubMedGoogle Scholar
  370. 370.
    Wei W, Chua MS, Grepper S, So S. Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int J Cancer. 2010;126:2426–36.PubMedGoogle Scholar
  371. 371.
    Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone diseases. Gene. 2004;341:19–39.PubMedGoogle Scholar
  372. 372.
    Wieser R, Wrana JL, Massagué J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J. 1995;14:2199–208.PubMedPubMedCentralGoogle Scholar
  373. 373.
    Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol. 1991;11:2057–65.PubMedPubMedCentralGoogle Scholar
  374. 374.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994;370:341–7.PubMedGoogle Scholar
  375. 375.
    Yang Y, Zhou L, Lu L, Wang L, Li X, Jiang P, Chan LK, Zhang T, Yu J, Kwong J, Cheung TH, Chung T, Mak K, Sun H, Wang H. A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma. Oncogene. 2013;32:3432–42.PubMedGoogle Scholar
  376. 376.
    Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 1996;10:1443–54.PubMedGoogle Scholar
  377. 377.
    Zhang S, Yu D. Targeting Src family kinases in anti-cancer therapies: turning promise into triumph. Trends Pharmacol Sci. 2012;33:122–8.PubMedGoogle Scholar
  378. 378.
    Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19:128–39.PubMedPubMedCentralGoogle Scholar
  379. 379.
    Zhao Y, Yang Y, Trovik J, Sun K, Zhou L, Jiang P, Lau TS, Hoivik EA, Salvesen HB, Sun H, Wang H. A novel wnt regulatory axis in endometrioid endometrial cancer. Cancer Res. 2014;74:5103–17.PubMedGoogle Scholar
  380. 380.
    Zhou J, Roh JW, Bandyopadhyay S, Chen Z, Munkarah AR, Hussein Y, Alosh B, Jazaerly T, Hayek K, Semaan A, Sood AK, Ali-Fehmi R. Overexpression of enhancer of zeste homolog 2 (EZH2) and focal adhesion kinase (FAK) in high grade endometrial carcinoma. Gynecol Oncol. 2013;128:344–8.PubMedGoogle Scholar
  381. 381.
    Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature. 1999;400:687–93.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Nuria Eritja
    • 1
    • 2
  • Andree Yeramian
    • 1
    • 2
  • Bo-Juen Chen
    • 3
  • David Llobet-Navas
    • 4
  • Eugenia Ortega
    • 1
  • Eva Colas
    • 1
    • 5
    • 2
  • Miguel Abal
    • 6
    • 2
  • Xavier Dolcet
    • 1
    • 2
  • Jaume Reventos
    • 5
    • 2
  • Xavier Matias-Guiu
    • 1
    • 2
  1. 1.Department of Pathology and Molecular Genetics and Research LaboratoryHospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDALleidaSpain
  2. 2.GEICEN Research Group, Department of Pathology and Molecular Genetics and Research LaboratoryHospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDALleidaSpain
  3. 3.New York Genome CenterNew YorkUSA
  4. 4.Institute of Genetic MedicineNewcastle UniversityNewcastle-Upon-TyneUK
  5. 5.Research Unit in Biomedicine and Translational and Pediatric OncologyVall d’Hebron Research InstituteBarcelonaSpain
  6. 6.Translational Medical Oncology, Health Research Institute of Santiago (IDIS)Santiago de CompostelaSpain

Personalised recommendations