Advertisement

The Dawning of Translational Breast Cancer: From Bench to Bedside

  • Xueman Chen
  • Siting Fan
  • Erwei SongEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1026)

Abstract

Breast cancer is one of the world’s leading causes of death in women. Although tumor initiation and progression are predominantly driven by somatic or acquired (epi) genetic alterations that govern signaling abnormalities, growing evidence suggests that the inflammatory microenvironments of cancer also play a role. Molecular characterization of breast cancer biology is essential for high-efficient management of this disease in clinical practice. Translating basic research into clinically valuable biomarkers for diagnosis, prognosis, and prediction of response to treatment and into precisely targeted therapies is crucial for the development of precision medicine in breast cancer. Such a process is known as “from bench to bedside.” In this chapter, we will present an overview of breast cancer pathogenesis and selected translational advances in multistage clinical settings and aim to illustrate the dawning of precision medicine implementation in managing human breast malignancies.

Keywords

Breast cancer Biological hallmark Translational oncology Precision medicine 

Notes

Conflict of Interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Prat A, Perou CM (2011) Deconstructing the molecular portraits of breast cancer. Mol Oncol 5(1):5–23PubMedCrossRefGoogle Scholar
  3. 3.
    Sotiriou C, Neo S-Y, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci 100(18):10393–10398PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA (2013) Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333–339PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hudson TJ, Anderson W, Aretz A, Barker AD, Bell C, Bernabé RR, Bhan M, Calvo F, Eerola I, Gerhard DS (2010) International network of cancer genome projects. Nature 464(7291):993–998PubMedCrossRefGoogle Scholar
  6. 6.
    Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826PubMedCrossRefGoogle Scholar
  7. 7.
    Fidler IJ, Poste G (2008) The “seed and soil” hypothesis revisited. Lancet Oncol 9(8):808PubMedCrossRefGoogle Scholar
  8. 8.
    Massagué J, Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529(7586):298–306PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A (2006) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25(1):118–145PubMedCrossRefGoogle Scholar
  10. 10.
    Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: ten years of targeted anti–HER-2 therapy and personalized medicine. Oncologist 14(4):320–368PubMedCrossRefGoogle Scholar
  11. 11.
    Nielsen DL, Andersson M, Kamby C (2009) HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Cancer Treat Rev 35(2):121–136PubMedCrossRefGoogle Scholar
  12. 12.
    Gschwind A, Fischer OM, Ullrich A (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 4(5):361–370PubMedCrossRefGoogle Scholar
  13. 13.
    Graus-Porta D, Beerli RR, Daly JM, Hynes NE (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16(7):1647–1655PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y (1996) A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16(10):5276–5287PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Roskoski R (2004) The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun 319(1):1–11PubMedCrossRefGoogle Scholar
  16. 16.
    Nahta R, Esteva FJ (2006) Herceptin: mechanisms of action and resistance. Cancer Lett 232(2):123–138PubMedCrossRefGoogle Scholar
  17. 17.
    Yeon CH, Pegram MD (2005) Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer. Investig New Drugs 23(5):391–409CrossRefGoogle Scholar
  18. 18.
    Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26(45):6469–6487PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K (2008) Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 26(35):5697–5704PubMedCrossRefGoogle Scholar
  20. 20.
    Piccart M, Lohrisch C, Di Leo A, Larsimont D (2001) The predictive value of HER2 in breast cancer. Oncology 61(Suppl. 2):73–82PubMedCrossRefGoogle Scholar
  21. 21.
    Yarden Y (2001) Biology of HER2 and its importance in breast cancer. Oncology 61(Suppl. 2):1–13PubMedCrossRefGoogle Scholar
  22. 22.
    Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 16(6):413–428PubMedCrossRefGoogle Scholar
  23. 23.
    Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L (2012) Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 9(1):16–32CrossRefGoogle Scholar
  24. 24.
    Carter P, Presta L, Gorman CM, Ridgway J, Henner D, Wong W, Rowland AM, Kotts C, Carver ME, Shepard HM (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci 89(10):4285–4289PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Tokuda Y, Ohnishi Y, Shimamura K, Iwasawa M, Yoshimura M, Ueyama Y, Tamaoki N, Tajima T, Mitomi T (1996) In vitro and in vivo anti-tumour effects of a humanised monoclonal antibody against c-erbB-2 product. Brit J Cancer 73(11):1362PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J (1998) Recombinant humanized anti-HER2 antibody (Herceptin™) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58(13):2825–2831PubMedGoogle Scholar
  27. 27.
    Vogel C, Cobleigh M, Tripathy D, Gutheil J, Harris L, Fehrenbacher L, Slamon D, Murphy M, Novotny W, Burchmore M (2001) First-line, single-agent Herceptin®(trastuzumab) in metastatic breast cancer: a preliminary report. Eur J Cancer 37:25–29PubMedCrossRefGoogle Scholar
  28. 28.
    Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A (2005) Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 23(19):4265–4274PubMedCrossRefGoogle Scholar
  29. 29.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684PubMedCrossRefGoogle Scholar
  30. 30.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672PubMedCrossRefGoogle Scholar
  31. 31.
    Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354(8):809–820PubMedCrossRefGoogle Scholar
  32. 32.
    Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369(9555):29–36PubMedCrossRefGoogle Scholar
  33. 33.
    Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT, Arteaga CL (2000) Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 60(20):5887–5894PubMedGoogle Scholar
  34. 34.
    Liang K, Lu Y, Jin W, Ang KK, Milas L, Fan Z (2003) Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther 2(11):1113–1120PubMedGoogle Scholar
  35. 35.
    Spector NL, Xia W, Burris H III, Hurwitz H, Dees EC, Dowlati A, O’neil B, Overmoyer B, Marcom PK, Blackwell KL (2005) Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J Clin Oncol 23(11):2502–2512PubMedCrossRefGoogle Scholar
  36. 36.
    Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ (2006) Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66(3):1630–1639PubMedCrossRefGoogle Scholar
  37. 37.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743PubMedCrossRefGoogle Scholar
  38. 38.
    Ross J, Gray G (2002) Targeted therapy for cancer: the HER-2/neu and Herceptin story. Clinical leadership & management review: the journal of CLMA 17(6):333–340Google Scholar
  39. 39.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792PubMedCrossRefGoogle Scholar
  40. 40.
    Xia W, Liu L-H, Ho P, Spector NL (2004) Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 23(3):646–653PubMedCrossRefGoogle Scholar
  41. 41.
    Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, Spector NL (2005) Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 24(41):6213–6221PubMedCrossRefGoogle Scholar
  42. 42.
    O’Donovan N, Byrne AT, O’Connor AE, McGee S, Gallagher WM, Crown J (2011) Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells. Investig New Drugs 29(5):752–759CrossRefGoogle Scholar
  43. 43.
    Baselga J, Bradbury I, Eidtmann H (2012) First results of the NeoaLTTO trial (BIG 01-06/EGF 106903): Lapatinib with Trastuzumab for HER2-positive early breast cancer (NeoaLTTO): a randomized open label multicenter phase 3 trial. Lancet (London, England) 379(9816):633–640CrossRefGoogle Scholar
  44. 44.
    Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4):395–402PubMedCrossRefGoogle Scholar
  45. 45.
    Nagata Y, Lan K-H, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127PubMedCrossRefGoogle Scholar
  46. 46.
    Wang Y, Liu Y, Du Y, Yin W, Lu J (2013) The predictive role of phosphatase and tensin homolog (PTEN) loss, phosphoinositol-3 (PI3) kinase (PIK3CA) mutation, and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis. Curr Med Res Opin 29(6):633–642PubMedCrossRefGoogle Scholar
  47. 47.
    Rexer BN, Arteaga CL (2012) Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Critical Rev Oncogen 17(1): 1–16Google Scholar
  48. 48.
    Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K, Fourme E, Lidereau R, Bièche I (2012) PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Res 14(1):R28PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Cizkova M, Dujaric M, Lehmann-Che J, Scott V, Tembo O, Asselain B, Pierga J, Marty M, De Cremoux P, Spyratos F (2013) Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Brit J Cancer 108(9):1807–1809PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Network CGA (2012) Comprehensive molecular portraits of human breast tumors. Nature 490(7418):61CrossRefGoogle Scholar
  51. 51.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554–554PubMedCrossRefGoogle Scholar
  52. 52.
    Janiszewska M, Liu L, Almendro V, Kuang Y, Paweletz C, Sakr RA, Weigelt B, Hanker AB, Chandarlapaty S, King TA (2015) In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer. Nature Publishing GroupGoogle Scholar
  53. 53.
    Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399PubMedGoogle Scholar
  54. 54.
    Tilch E, Seidens T, Cocciardi S, Reid L, Byrne D, Simpson P, Vargas A, Cummings M, Fox S, Lakhani S (2014) Mutations in EGFR, BRAF and RAS are rare in triple-negative and basal-like breast cancers from Caucasian women. Breast Cancer Res Treat 143(2):385–392PubMedCrossRefGoogle Scholar
  55. 55.
    Koren S, Reavie L, Couto JP, De Silva D, Stadler MB, Roloff T, Britschgi A, Eichlisberger T, Kohler H, Aina O (2015) PIK3CAH1047R induces multipotency and multi-lineage mammary tumours. Nature 525(7567):114–118PubMedCrossRefGoogle Scholar
  56. 56.
    Koren S, Bentires-Alj M (2013) Mouse models of PIK3CA mutations: one mutation initiates heterogeneous mammary tumors. FEBS J 280(12):2758–2765PubMedCrossRefGoogle Scholar
  57. 57.
    Meyer DS, Brinkhaus H, Müller U, Müller M, Cardiff RD, Bentires-Alj M (2011) Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res 71(13):4344–4351PubMedCrossRefGoogle Scholar
  58. 58.
    Liu P, Cheng H, Santiago S, Raeder M, Zhang F, Isabella A, Yang J, Semaan DJ, Chen C, Fox EA (2011) Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med 17(9):1116–1120PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, Van De Rijn M, Jeffrey SS (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci 98(19):10869–10874PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Ma CX, Reinert T, Chmielewska I, Ellis MJ (2015) Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 15(5):261–275. doi: 10.1038/nrc3920 PubMedCrossRefGoogle Scholar
  61. 61.
    Donehower LA, Harvey M (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366):215PubMedCrossRefGoogle Scholar
  62. 62.
    Kuperwasser C, Hurlbut GD, Kittrell FS, Dickinson ES, Laucirica R, Medina D, Naber SP, Jerry DJ (2000) Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice: a model for li-Fraumeni syndrome. Am J Pathol 157(6):2151–2159PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Van Keymeulen A, Lee MY, Ousset M, Brohée S, Rorive S, Giraddi RR, Wuidart A, Bouvencourt G, Dubois C, Salmon I (2015) Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature 525(7567):119–123PubMedCrossRefGoogle Scholar
  64. 64.
    Greenblatt MS, Chappuis PO, Bond JP, Hamel N, Foulkes WD (2001) TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations. Cancer Res 61(10):4092–4097PubMedGoogle Scholar
  65. 65.
    Drost R, Jonkers J (2009) Preclinical mouse models for BRCA1-associated breast cancer. Brit J Cancer 101(10):1651–1657PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Johannsson O, Idvall I, Anderson C, Borg Å, Barkardottir R, Egilsson V, Olsson H (1997) Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 33(3):362–371PubMedCrossRefGoogle Scholar
  67. 67.
    Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM (1997) Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88(2):265–275PubMedCrossRefGoogle Scholar
  68. 68.
    Moynahan ME, Chiu JW, Koller BH, Jasin M (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4(4):511–518PubMedCrossRefGoogle Scholar
  69. 69.
    Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP (2004) The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96(22):1659–1668PubMedCrossRefGoogle Scholar
  70. 70.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921PubMedCrossRefGoogle Scholar
  71. 71.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’connor MJ (2009) Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134PubMedCrossRefGoogle Scholar
  72. 72.
    Deng C-X (2006) BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res 34(5):1416–1426PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Mullan P, Quinn J, Harkin D (2006) The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene 25(43):5854–5863PubMedCrossRefGoogle Scholar
  74. 74.
    Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, Mok SC, Randrianarison V, Brodie S, Salstrom J (2002) BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 111(3):393–405PubMedCrossRefGoogle Scholar
  75. 75.
    Sørlie T, Tibshirani R, Parker J, Hastie T, Marron J, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci 100(14):8418–8423PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15(8):907–913. doi: 10.1038/nm.2000 PubMedCrossRefGoogle Scholar
  77. 77.
    Proia TA, Keller PJ, Gupta PB, Klebba I, Jones AD, Sedic M, Gilmore H, Tung N, Naber SP, Schnitt S (2011) Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 8(2):149–163PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Molyneux G, Geyer FC, Magnay F-A, McCarthy A, Kendrick H, Natrajan R, MacKay A, Grigoriadis A, Tutt A, Ashworth A (2010) BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3):403–417PubMedCrossRefGoogle Scholar
  79. 79.
    Bai F, Smith M, Chan H, Pei X (2013) Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation. Oncogene 32(22):2715–2725PubMedCrossRefGoogle Scholar
  80. 80.
    Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366(1):2–16PubMedCrossRefGoogle Scholar
  81. 81.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354PubMedCrossRefGoogle Scholar
  82. 82.
    Harris RC, Chung E, Coffey RJ (2004) EGF receptor ligands. The EGF receptor family biologic mechanisms and role in cancer Elsevier, California, pp 3–14Google Scholar
  83. 83.
    Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield M (1984) Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307(5951):521–527PubMedCrossRefGoogle Scholar
  84. 84.
    Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137PubMedCrossRefGoogle Scholar
  85. 85.
    Arteaga CL (2001) The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 19 (Suppl 1):32s-40sGoogle Scholar
  86. 86.
    Hynes NE, MacDonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21(2):177–184PubMedCrossRefGoogle Scholar
  87. 87.
    Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284(1):31–53PubMedCrossRefGoogle Scholar
  88. 88.
    Nicholson R, Gee J, Harper M (2001) EGFR and cancer prognosis. Eur J Cancer 37:9–15CrossRefGoogle Scholar
  89. 89.
    Bange J, Zwick E, Ullrich A (2001) Molecular targets for breast cancer therapy and prevention. Nat Med 7(5):548PubMedCrossRefGoogle Scholar
  90. 90.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139PubMedCrossRefGoogle Scholar
  91. 91.
    Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500PubMedCrossRefGoogle Scholar
  92. 92.
    Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101(36):13306–13311PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Ali S, Wang K, Johnson A, Rodriguez A, Elvin J, Vergilio J, Suh J, Chumsri S, Morosini D, Yelensky R (2016) Abstract P6-03-02: EGFR genomic alterations in 5605 cases of refractory and metastatic breast cancer. AACRGoogle Scholar
  94. 94.
    Thomas SM, Grandis JR (2004) Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors under clinical investigation. Cancer Treat Rev 30(3):255–268PubMedCrossRefGoogle Scholar
  95. 95.
    Ranson M, Hammond LA, Ferry D, Kris M, Tullo A, Murray PI, Miller V, Averbuch S, Ochs J, Morris C (2002) ZD1839, a selective oral epidermal growth factor receptor–tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 20(9):2240–2250PubMedCrossRefGoogle Scholar
  96. 96.
    Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, Eckhardt SG, Tolcher A, Britten CD, Denis L (2001) Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19(13):3267–3279PubMedCrossRefGoogle Scholar
  97. 97.
    Hong WK, Ullrich A (2000) The role of EGFR in solid tumors and implications for therapy. Oncol Biother 1(1):1–29Google Scholar
  98. 98.
    Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S, Bianco AR, Tortora G (2000) Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6(5):2053–2063PubMedGoogle Scholar
  99. 99.
    Baselga J, Albanell J, Ruiz A, Lluch A, Gascón P, Guillém V, González S, Sauleda S, Marimón I, Tabernero JM (2005) Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23(23):5323–5333PubMedCrossRefGoogle Scholar
  100. 100.
    Ciardiello F, Troiani T, Caputo F, De Laurentiis M, Palmieri G, Colantuoni G, Diadema M, De Placido S, Bianco A (2004) A phase II study of gefitinib combined with docetaxel as first-line treatment in patients with advanced breast cancer. J Clin Oncol 22:58sGoogle Scholar
  101. 101.
    Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, Rimawi MF, Forero-Torres A (2012) TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 30(21):2615–2623PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Moulder SL, Arteaga CL (2003) A phase I/II trial of trastuzumab and gefitinib in patients with metastatic breast cancer that overexpresses HER2/neu (ErbB-2). Clin Breast Cancer 4(2):142–145PubMedCrossRefGoogle Scholar
  103. 103.
    Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, Williams LS, Di Leo A (2009) Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol 27(24):3908–3915PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Musgrove EA, Sutherland RL (2009) Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 9(9):631–643PubMedCrossRefGoogle Scholar
  105. 105.
    Manavathi B, Dey O, Gajulapalli VNR, Bhatia RS, Bugide S, Kumar R (2012) Derailed estrogen signaling and breast cancer: an authentic couple. Endocr Rev 34(1):1–32PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Clarke R, Tyson JJ, Dixon JM (2015) Endocrine resistance in breast cancer–an overview and update. Mol Cell Endocrinol 418:220–234PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Clarke R, Leonessa F, Welch JN, Skaar TC (2001) Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev 53(1):25–72PubMedGoogle Scholar
  108. 108.
    Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2–positive breast cancer. J Natl Cancer Inst 96(12):926–935PubMedCrossRefGoogle Scholar
  109. 109.
    Nicholson RI, Hutcheson IR, Knowlden JM, Jones HE, Harper ME, Jordan N, Hiscox SE, Barrow D, Gee JM (2004) Nonendocrine pathways and endocrine resistance. Clin Cancer Res 10(1):346s–354sGoogle Scholar
  110. 110.
    Okubo S, Kurebayashi J, Otsuki T, Yamamoto Y, Tanaka K, Sonoo H (2004) Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells. Brit J Cancer 90(1):236–244PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Streuli CH, Akhtar N (2009) Signal co-operation between integrins and other receptor systems. Biochem J 418(3):491–506PubMedCrossRefGoogle Scholar
  112. 112.
    Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69(1):11–25PubMedCrossRefGoogle Scholar
  113. 113.
    Ginsberg MH, Du X, Plow EF (1992) Inside-out integrin signalling. Curr Opin Cell Biol 4(5):766–771PubMedCrossRefGoogle Scholar
  114. 114.
    Glukhova MA, Streuli CH (2013) How integrins control breast biology. Curr Opin Cell Biol 25(5):633–641PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Koukoulis G, Virtanen I, Korhonen M, Laitinen L, Quaranta V, Gould V (1991) Immunohistochemical localization of integrins in the normal, hyperplastic, and neoplastic breast. Correlations with their functions as receptors and cell adhesion molecules. Am J Pathol 139(4):787PubMedPubMedCentralGoogle Scholar
  116. 116.
    Lu S, Simin K, Khan A, Mercurio AM (2008) Analysis of integrin β4 expression in human breast cancer: association with basal-like tumors and prognostic significance. Clin Cancer Res 14(4):1050–1058PubMedCrossRefGoogle Scholar
  117. 117.
    Pontiggia O, Sampayo R, Raffo D, Motter A, Xu R, Bissell MJ, de Kier Joffé EB, Simian M (2012) The tumor microenvironment modulates tamoxifen resistance in breast cancer: a role for soluble stromal factors and fibronectin through β1 integrin. Breast Cancer Res Treat 133(2):459–471PubMedCrossRefGoogle Scholar
  118. 118.
    Lesniak D, Xu Y, Deschenes J, Lai R, Thoms J, Murray D, Gosh S, Mackey JR, Sabri S, Abdulkarim B (2009) β1-integrin circumvents the Antiproliferative effects of Trastuzumab in human epidermal growth factor receptor-2–positive breast cancer. Cancer Res 69(22):8620–8628PubMedCrossRefGoogle Scholar
  119. 119.
    Jahangiri A, Aghi MK, Carbonell WS (2014) β1 integrin: critical path to antiangiogenic therapy resistance and beyond. Cancer Res 74(1):3–7PubMedCrossRefGoogle Scholar
  120. 120.
    Nisticò P, Di Modugno F, Spada S, Bissell MJ (2014) β1 and β4 integrins: from breast development to clinical practice. Breast Cancer Res 16(5):459PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Thundimadathil J (2012) Cancer treatment using peptides: current therapies and future prospects. J Amino Acids 2012:1–13Google Scholar
  122. 122.
    Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26(22):3291–3310PubMedCrossRefGoogle Scholar
  123. 123.
    Samatar AA, Poulikakos PI (2014) Targeting RAS–ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov 13(12):928–942PubMedCrossRefGoogle Scholar
  124. 124.
    Rowinsky EK, Windle JJ, Von Hoff DD (1999) Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 17(11):3631–3652PubMedCrossRefGoogle Scholar
  125. 125.
    Craig DW, O’Shaughnessy JA, Kiefer JA, Aldrich J, Sinari S, Moses TM, Wong S, Dinh J, Christoforides A, Blum JL (2013) Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther 12(1):104–116PubMedCrossRefGoogle Scholar
  126. 126.
    Caunt CJ, Sale MJ, Smith PD, Cook SJ (2015) MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer 15(10):577–592PubMedCrossRefGoogle Scholar
  127. 127.
    Rinehart J, Adjei AA, LoRusso PM, Waterhouse D, Hecht JR, Natale RB, Hamid O, Varterasian M, Asbury P, Kaldjian EP (2004) Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 22(22):4456–4462PubMedCrossRefGoogle Scholar
  128. 128.
    Ihle NT, Lemos R, Wipf P, Yacoub A, Mitchell C, Siwak D, Mills GB, Dent P, Kirkpatrick DL, Powis G (2009) Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 69(1):143–150PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562PubMedCrossRefGoogle Scholar
  130. 130.
    Thorpe LM, Yuzugullu H, Zhao JJ (2015) PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15(1):7–24PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Gil EMC (2014) Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev 40(7):862–871CrossRefGoogle Scholar
  132. 132.
    Miller TW, Balko JM, Arteaga CL (2011) Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 29(33):4452–4461PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Karlsson E, Pérez-Tenorio G, Amin R, Bostner J, Skoog L, Fornander T, Sgroi DC, Nordenskjöld B, Hallbeck A-L, Stål O (2013) The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials. Breast Cancer Res 15(5):R96PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Bostner J, Karlsson E, Pandiyan MJ, Westman H, Skoog L, Fornander T, Nordenskjöld B, Stål O (2013) Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit. Breast Cancer Res Treat 137(2):397–406PubMedCrossRefGoogle Scholar
  135. 135.
    Beelen K, Opdam M, Severson TM, Koornstra RH, Vincent AD, Wesseling J, Muris JJ, Berns EM, Vermorken JB, van Diest PJ (2014) Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment. Breast Cancer Res 16(1):3362Google Scholar
  136. 136.
    Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor α a new model for anti-estrogen resistance. J Biol Chem 276(13):9817–9824PubMedCrossRefGoogle Scholar
  137. 137.
    Chen D, Washbrook E, Sarwar N, Bates GJ, Pace PE, Thirunuvakkarasu V, Taylor J, Epstein RJ, Fuller-Pace FV, Egly J-M (2002) Phosphorylation of human estrogen receptor [alpha] at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera. Oncogene 21(32):4921PubMedCrossRefGoogle Scholar
  138. 138.
    Fan P, Wang J, Santen RJ, Yue W (2007) Long-term treatment with tamoxifen facilitates translocation of estrogen receptor α out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res 67(3):1352–1360PubMedCrossRefGoogle Scholar
  139. 139.
    Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ (2004) The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane. Proc Natl Acad Sci 101(7):2076–2081PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Lim S, Kaldis P (2013) Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 140(15):3079–3093PubMedCrossRefGoogle Scholar
  141. 141.
    Roy PG, Pratt N, Purdie CA, Baker L, Ashfield A, Quinlan P, Thompson AM (2010) High CCND1 amplification identifies a group of poor prognosis women with estrogen receptor positive breast cancer. Int J Cancer 127(2):355–360PubMedGoogle Scholar
  142. 142.
    Nevins JR (1998) Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 9(8):585–593Google Scholar
  143. 143.
    Burkhart DL, Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8(9):671–682. doi: 10.1038/nrc2399 PubMedCrossRefGoogle Scholar
  144. 144.
    Sherr CJ, Beach D, Shapiro GI (2016) Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6(4):353–367PubMedCrossRefGoogle Scholar
  145. 145.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512PubMedCrossRefGoogle Scholar
  146. 146.
    Blain S (2008) Switching cyclin D-Cdk4 kinase activity on and off. Cell Cycle 7(7):892–898PubMedCrossRefGoogle Scholar
  147. 147.
    Murphy CG, Dickler MN (2015) The role of CDK4/6 inhibition in breast cancer. Oncologist 20(5):483–490PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES (2010) RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 9(20):4153–4163. doi: 10.4161/cc.9.20.13454 PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW (2006) Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9(1):13–22. doi: 10.1016/j.ccr.2005.12.019 PubMedCrossRefGoogle Scholar
  150. 150.
    Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411(6841):1017–1021. doi: 10.1038/35082500 PubMedCrossRefGoogle Scholar
  151. 151.
    Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P (2006) Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9(1):23–32. doi: 10.1016/j.ccr.2005.12.012 PubMedCrossRefGoogle Scholar
  152. 152.
    Sabbah M, Courilleau D, Mester J, Redeuilh G (1999) Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc Natl Acad Sci U S A 96(20):11217–11222PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ (1997) CDK-independent activation of estrogen receptor by cyclin D1. Cell 88(3):405–415PubMedCrossRefGoogle Scholar
  154. 154.
    Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES (2010) Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29(28):4018–4032. doi: 10.1038/onc.2010.154 PubMedCrossRefGoogle Scholar
  155. 155.
    Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, Zirkelbach JF, Yu J, Liu Q, Zhao L (2015) FDA approval: Palbociclib for the treatment of postmenopausal patients with estrogen receptor–positive, HER2-negative metastatic breast cancer. Clin Cancer Res 21(21):4760–4766PubMedCrossRefGoogle Scholar
  156. 156.
    Walker AJ, Wedam S, Amiri-Kordestani L, Bloomquist E, Tang S, Sridhara R, Chen W, Palmby TR, Zirkelbach JF, Fu W (2016) FDA approval of Palbociclib in combination with Fulvestrant for the treatment of hormone receptor–positive, HER2-negative metastatic breast cancer. Clin Cancer Res 22(20):4968–4972PubMedCrossRefGoogle Scholar
  157. 157.
    Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O’Dwyer PJ, Schwartz GK (2012) Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 18(2):568–576. doi: 10.1158/1078-0432.ccr-11-0509 CrossRefGoogle Scholar
  158. 158.
    Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL (2004) Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3(11):1427–1438PubMedGoogle Scholar
  159. 159.
    Munster PN, Hamilton EP, Franklin C, Bhansali S, Wan K, Hewes B, Juric D (2014) Phase lb study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2− BC). American Society of Clinical OncologyGoogle Scholar
  160. 160.
    Bardia A, Modi S, Chavez-Mac Gregor M, Kittaneh M, Marino AJ, Matano A, Bhansali S, Hewes B, Cortes J (2014) Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal women with ER+/HER2-metastatic breast cancer. American Society of Clinical OncologyGoogle Scholar
  161. 161.
    Dickler M, Tolaney S, Rugo H, Cortes J, Dieras V, Patt D, Wildiers H, Frenzel M, Koustenis A, Baselga J (2016) MONARCH1: results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2-breast cancer, after chemotherapy for advanced disease. J Clin Oncol 34(Suppl; abstr 510)Google Scholar
  162. 162.
    Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1(1):27–30PubMedCrossRefGoogle Scholar
  163. 163.
    Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Ribatti D, Nico B, Crivellato E, Roccaro A, Vacca A (2007) The history of the angiogenic switch concept. Leukemia 21(1):44–52PubMedCrossRefGoogle Scholar
  165. 165.
    Yarden Y, Baselga J, Miles D (2004) Molecular approach to breast cancer treatment. In: Seminars in oncology. Elsevier, Amsterdam, pp 6–13Google Scholar
  166. 166.
    Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69(Suppl. 3):4–10PubMedCrossRefGoogle Scholar
  167. 167.
    Baeriswyl V, Christofori G (2009) The angiogenic switch in carcinogenesis. In: Seminars in cancer biology, vol 5. Elsevier, Amsterdam, pp 329–337Google Scholar
  168. 168.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410PubMedCrossRefGoogle Scholar
  169. 169.
    Poon RT-P, Fan S-T, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19(4):1207–1225PubMedCrossRefGoogle Scholar
  170. 170.
    Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56(20):4625–4629PubMedGoogle Scholar
  171. 171.
    Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J (2014) Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. The regulation of angiogenesis by tissue cell-macrophage interactions: 63Google Scholar
  172. 172.
    Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370PubMedCrossRefGoogle Scholar
  173. 173.
    Gasparini G, Longo R, Toi M, Ferrara N (2005) Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat Clin Pract Oncol 2(11):562–577PubMedCrossRefGoogle Scholar
  174. 174.
    Miller K, Burstein H, Elias A, Rugo H, Cobleigh M, Pegram M, Eisenberg P, Collier M, Adams B, Baum C (2005) Phase II study of SU11248, a multitargeted receptor tyrosine kinase inhibitor (TKI), in patients (pts) with previously treated metastatic breast cancer (MBC). J Clin Oncol 23(90160):563–563CrossRefGoogle Scholar
  175. 175.
    Bianchi G, Loibl S, Zamagni C, Ardizzoni A, Raab G, Siena S, Wolf C, Westermeier T, Bergamini L, Gianni L (2005) A phase II multicentre uncontrolled trial of sorafenib (BAY 43–9006) in patients with metastatic breast cancer. In: EJC Supplements, vol 2. Pergamon-Elsevier Science Ltd, Oxford, pp 78–78Google Scholar
  176. 176.
    Eckhardt BL, Francis PA, Parker BS, Anderson RL (2012) Strategies for the discovery and development of therapies for metastatic breast cancer. Nat Rev Drug Discov 11(6):479–497. doi: 10.1038/nrd2372 PubMedCrossRefGoogle Scholar
  177. 177.
    Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM (2009) CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16(2):91–102PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Gocheva V, Wang H-W, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T, Joyce JA (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24(3):241–255PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124(2):263–266PubMedCrossRefGoogle Scholar
  181. 181.
    Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64(19):7022–7029PubMedCrossRefGoogle Scholar
  182. 182.
    Wyckoff JB, Wang Y, Lin EY, J-f L, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67(6):2649–2656PubMedCrossRefGoogle Scholar
  183. 183.
    Qian B-Z, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829PubMedCrossRefGoogle Scholar
  185. 185.
    Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, Weinberg RA (2015) Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525(7568):256–260. doi: 10.1038/nature14897 PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Su S, Liu Q, Chen J, Chen J, Chen F, He C, Huang D, Wu W, Lin L, Huang W (2014) A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25(5):605–620PubMedCrossRefGoogle Scholar
  187. 187.
    Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, Liu B, Deng H, Wang F, Lin L (2011) CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19(4):541–555PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174PubMedCrossRefGoogle Scholar
  189. 189.
    Dano K, Behrendt N, Hoyer-Hansen G, Johnsen M, Lund LR, Ploug M, Romer J (2005) Plasminogen activation and cancer. Thromb Haemost 93(4):676–681PubMedGoogle Scholar
  190. 190.
    Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56PubMedCrossRefGoogle Scholar
  191. 191.
    Mego M, Mani SA, Cristofanilli M (2010) Molecular mechanisms of metastasis in breast cancer—clinical applications. Nat Rev Clin Oncol 7(12):693–701PubMedCrossRefGoogle Scholar
  192. 192.
    Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9(4):285–293PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF, Huelsken J (2012) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481(7379):85–89. doi: 10.1038/nature10694 CrossRefGoogle Scholar
  194. 194.
    Alix-Panabieres C, Schwarzenbach H, Pantel K (2012) Circulating tumor cells and circulating tumor DNA. Annu Rev Med 63:199–215. doi: 10.1146/annurev-med-062310-094219 PubMedCrossRefGoogle Scholar
  195. 195.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, Seoane J (2013) Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nat Rev Clin Oncol 10(7):377–389. doi: 10.1038/nrclinonc.2013.80 PubMedCrossRefGoogle Scholar
  197. 197.
    Hagenbeck C, Melcher CA, Janni JW, Schneeweiss A, Fasching PA, Aktas B, Pantel K, Solomayer E-F, Ortmann U, Jaeger BAS (2012) DETECT III: a multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients (pts) with initially HER2-negative metastatic breast cancer but with HER2-positive circulating tumor cells (CTC). American Society of Clinical OncologyGoogle Scholar
  198. 198.
    Bidard F-C, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabières C, Janni W, Messina C, Paoletti C, Müller V, Hayes DF (2013) Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev 32(1–2):179–188PubMedCrossRefGoogle Scholar
  199. 199.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570PubMedCrossRefGoogle Scholar
  200. 200.
    Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, Solbach C, Hanker L, Ahr A, Metzler D (2009) T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res 11(2):R15PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    DeNardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9(4):212PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, Valero V, Cristofanilli M, Green MC, Radvanyi L (2010) Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor–positive and–negative cancers. J Clin Oncol 28(28):4316–4323PubMedCrossRefGoogle Scholar
  203. 203.
    Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518–527PubMedCrossRefGoogle Scholar
  204. 204.
    Bianchini G, Gianni L (2014) The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol 15(2):e58–e68PubMedCrossRefGoogle Scholar
  205. 205.
    Stagg J, Loi S, Divisekera U, Ngiow SF, Duret H, Yagita H, Teng MW, Smyth MJ (2011) Anti–ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti–PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci 108(17):7142–7147PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Wang Q, Li S-H, Wang H, Xiao Y, Sahin O, Brady SW, Li P, Ge H, Jaffee EM, Muller WJ (2012) Concomitant targeting of tumor cells and induction of T-cell response synergizes to effectively inhibit trastuzumab-resistant breast cancer. Cancer Res 72(17):4417–4428PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Dolled-Filhart M, Emancipator K, Gonzalez EJ (2015) Abstract S1–09: a phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. AACRGoogle Scholar
  208. 208.
    Mittendorf EA, Clifton GT, Holmes JP, Clive KS, Patil R, Benavides LC, Gates JD, Sears AK, Stojadinovic A, Ponniah S (2012) Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients. Cancer 118(10):2594–2602PubMedCrossRefGoogle Scholar
  209. 209.
    Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM (2014) Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33(6):540–549PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967):517–528PubMedCrossRefGoogle Scholar
  211. 211.
    Brookes E, Shi Y (2014) Diverse epigenetic mechanisms of human disease. Annu Rev Genet 48:237–268PubMedCrossRefGoogle Scholar
  212. 212.
    Bjornsson HT, Fallin MD, Feinberg AP (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet 20(8):350–358PubMedCrossRefGoogle Scholar
  213. 213.
    Woods K, Thomson JM, Hammond SM (2007) Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J Biol Chem 282(4):2130–2134PubMedCrossRefGoogle Scholar
  214. 214.
    Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283(2):1026–1033PubMedCrossRefGoogle Scholar
  215. 215.
    Dinami R, Ercolani C, Petti E, Piazza S, Ciani Y, Sestito R, Sacconi A, Biagioni F, le Sage C, Agami R (2014) miR-155 drives telomere fragility in human breast cancer by targeting TRF1. Cancer Res 74(15):4145–4156PubMedCrossRefGoogle Scholar
  216. 216.
    Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J (2007) Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131(6):1109–1123PubMedCrossRefGoogle Scholar
  217. 217.
    Lin X, Chen L, Yao Y, Zhao R, Cui X, Chen J, Hou K, Zhang M, Su F, Chen J (2015) CCL18-mediated down-regulation of miR98 and miR27b promotes breast cancer metastasis. Oncotarget 6(24):20485PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Kato M, Paranjape T, Ullrich R, Nallur S, Gillespie E, Keane K, Esquela-Kerscher A, Weidhaas J, Slack F (2009) The mir-34 microRNA is required for the DNA damage response in vivo in C. elegans and in vitro in human breast cancer cells. Oncogene 28(25):2419–2424PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Yang S, Li Y, Gao J, Zhang T, Li S, Luo A, Chen H, Ding F, Wang X, Liu Z (2013) MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene 32(36):4294–4303PubMedCrossRefGoogle Scholar
  220. 220.
    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai M-C, Hung T, Argani P, Rinn JL (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464(7291):1071–1076PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 43(7):621–629PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Mourtada-Maarabouni M, Pickard M, Hedge V, Farzaneh F, Williams G (2009) GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 28(2):195–208PubMedCrossRefGoogle Scholar
  223. 223.
    Latorre E, Carelli S, Raimondi I, D’Agostino V, Castiglioni I, Zucal C, Moro G, Luciani A, Ghilardi G, Monti E (2016) The ribonucleic complex HuR-MALAT1 represses CD133 expression and suppresses epithelial–mesenchymal transition in breast cancer. Cancer Res 76(9):2626–2636PubMedCrossRefGoogle Scholar
  224. 224.
    Su F, Li D, Zeng M, Song E (2015) A cytoplasmic NF-kB interacting long noncoding RNA blocks IkB phosphorylation and suppresses breast cancer metastasis. Cancer Cell 27:370–381PubMedCrossRefGoogle Scholar
  225. 225.
    Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X, Huang S (2015) Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 25(8):981PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Zhang H, Ren Y, Xu H, Pang D, Duan C, Liu C (2013) The expression of stem cell protein Piwil2 and piR-932 in breast cancer. Surg Oncol 22(4):217–223. doi: 10.1016/j.suronc.2013.07.001 PubMedCrossRefGoogle Scholar
  227. 227.
    Pichler M, Calin GA (2015) MicroRNAs in cancer: from developmental genes in worms to their clinical application in patients. Brit J Cancer 113(4):569–573. doi: 10.1038/bjc.2015.253 PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Chen X, Liu Q, Song E (2017) Mammary stem cells: angels or demons in mammary gland? Sig Transduct Target Therapy 2:16038CrossRefGoogle Scholar
  229. 229.
    Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA, Eckhardt SG (2012) Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 9(6):338–350PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Breast Tumor Center, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  2. 2.Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  3. 3.Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou, GuangdongChina

Personalised recommendations