Pharmacologic Interventions with NSAIDs

  • Louise R. HoweEmail author
Part of the Energy Balance and Cancer book series (EBAC, volume 7)


Obesity as a determinant of increased cancer risk and poorer cancer outcome is well established for cancers of several organ sites, including colorectal and postmenopausal breast cancer. Obesity-associated adipose inflammation leads to local and systemic accumulation of inflammatory mediators and hormones, which have multiple proneoplastic effects. Key among these from a pharmacological perspective are cyclooxygenase (COX)-derived prostaglandins (PGs), since COX enzymes are the primary target for nonsteroidal anti-inflammatory drugs (NSAIDs). Overexpression of the inducible PG synthase COX-2 occurs in the majority of colorectal neoplasias and ~40 % of breast cancers and is also evident in inflamed adipose tissue from obese mice and humans. COX/PG signaling has multiple protumorigenic consequences, which provide at least a partial explanation for epidemiologic and experimental observations of reduced cancer risk associated with NSAID use. Notably, COX/PG-mediated upregulation of estrogen biosynthesis and signaling offers a plausible target for NSAID-mediated risk reduction with respect to breast and other hormone-sensitive cancers. Additionally, “off-target” NSAID effects including modulation of NFκB and AMP kinase activity may be of particular significance in the context of obesity. NSAID-mediated amelioration of obesity-­related metabolic dysfunction has been reported, and it seems likely that NSAIDs will be similarly protective for obesity-associated carcinogenesis.


Breast Cancer Breast Cancer Risk Colorectal Adenoma Increase Breast Cancer Risk Colorectal Neoplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Calle EE, Thun MJ (2004) Obesity and cancer. Oncogene 23(38):6365–6378. doi:10.1038/sj.onc.1207751 1207751 [pii]PubMedGoogle Scholar
  2. 2.
    Wolin KY, Carson K, Colditz GA (2010) Obesity and cancer. Oncologist 15(6):556–565. doi:theoncologist.2009-0285 [pii] 10.1634/theoncologist.2009-0285PubMedGoogle Scholar
  3. 3.
    World Cancer Research Fund/American Institute for Cancer Research (2007) Food nutrition, physical activity, and the prevention of cancer: a global perspective. World Cancer Research Fund/American Institute for Cancer Research, Washington, DCGoogle Scholar
  4. 4.
    Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18(3):363–374. doi:nm.2627 [pii] 10.1038/nm.2627PubMedGoogle Scholar
  5. 5.
    van Kruijsdijk RC, van der Wall E, Visseren FL (2009) Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 18(10):2569–2578. doi:1055–9965.EPI-09-0372 [pii] 10.1158/1055-9965.EPI-09-0372PubMedGoogle Scholar
  6. 6.
    Smith WL, Urade Y, Jakobsson PJ (2011) Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis. Chem Rev 111(10):5821–5865. doi: 10.1021/cr2002992 PubMedGoogle Scholar
  7. 7.
    Herschman HR (1996) Prostaglandin synthase 2. Biochim Biophys Acta 1299(1):125–140PubMedGoogle Scholar
  8. 8.
    Brown JR, DuBois RN (2005) COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol 23(12):2840–2855. doi:23/12/2840 [pii] 10.1200/JCO.2005.09.051PubMedGoogle Scholar
  9. 9.
    Howe LR, Subbaramaiah K, Brown AMC, Dannenberg AJ (2001) Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocr Relat Cancer 8(2):97–114PubMedGoogle Scholar
  10. 10.
    Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107(4):1183–1188PubMedGoogle Scholar
  11. 11.
    Kargman SL, O’Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S (1995) Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res 55(12):2556–2559PubMedGoogle Scholar
  12. 12.
    Sano H, Kawahito Y, Wilder RL, Hashiramoto A, Mukai S, Asai K, Kimura S, Kato H, Kondo M, Hla T (1995) Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55(17):3785–3789PubMedGoogle Scholar
  13. 13.
    Kutchera W, Jones DA, Matsunami N, Groden J, McIntyre TM, Zimmerman GA, White RL, Prescott SM (1996) Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc Natl Acad Sci U S A 93(10):4816–4820PubMedGoogle Scholar
  14. 14.
    Boolbol SK, Dannenberg AJ, Chadburn A, Martucci C, Guo XJ, Ramonetti JT, Abreu-Goris M, Newmark HL, Lipkin ML, DeCosse JJ, Bertagnolli MM (1996) Cyclooxygenase-2 ­overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 56(11):2556–2560PubMedGoogle Scholar
  15. 15.
    Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF, Taketo MM (1996) Suppression of intestinal polyposis in Apc∆716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87(5):803–809PubMedGoogle Scholar
  16. 16.
    Williams CS, Luongo C, Radhika A, Zhang T, Lamps LW, Nanney LB, Beauchamp RD, DuBois RN (1996) Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 111(4):1134–1140PubMedGoogle Scholar
  17. 17.
    DuBois RN, Radhika A, Reddy BS, Entingh AJ (1996) Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors. Gastroenterology 110(4):1259–1262PubMedGoogle Scholar
  18. 18.
    Singh J, Hamid R, Reddy BS (1997) Dietary fat and colon cancer: modulation of cyclooxygenase-­2 by types and amount of dietary fat during the postinitiation stage of colon carcinogenesis. Cancer Res 57(16):3465–3470PubMedGoogle Scholar
  19. 19.
    Chapple KS, Cartwright EJ, Hawcroft G, Tisbury A, Bonifer C, Scott N, Windsor AC, Guillou PJ, Markham AF, Coletta PL, Hull MA (2000) Localization of cyclooxygenase-2 in human sporadic colorectal adenomas. Am J Pathol 156(2):545–553. doi:S0002-­9440(10)64759-1 [pii] 10.1016/S0002-9440(10)64759-1PubMedGoogle Scholar
  20. 20.
    Hull MA, Booth JK, Tisbury A, Scott N, Bonifer C, Markham AF, Coletta PL (1999) Cyclooxygenase 2 is up-regulated and localized to macrophages in the intestine of Min mice. Br J Cancer 79(9–10):1399–1405. doi: 10.1038/sj.bjc.6690224 PubMedGoogle Scholar
  21. 21.
    Martinez ME, Heddens D, Earnest DL, Bogert CL, Roe D, Einspahr J, Marshall JR, Alberts DS (1999) Physical activity, body mass index, and prostaglandin E2 levels in rectal mucosa. J Natl Cancer Inst 91(11):950–953PubMedGoogle Scholar
  22. 22.
    Bennett A, Charlier EM, McDonald AM, Simpson JS, Stamford IF, Zebro T (1977) Prostaglandins and breast cancer. Lancet 2(8039):624–626. doi:S0140-6736(77)92496-5 [pii]PubMedGoogle Scholar
  23. 23.
    Rolland PH, Martin PM, Jacquemier J, Rolland AM, Toga M (1980) Prostaglandin in human breast cancer: evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells. J Natl Cancer Inst 64(5):1061–1070PubMedGoogle Scholar
  24. 24.
    Tan WC, Privett OS, Goldyne ME (1974) Studies of prostaglandins in rat mammary tumors induced by 7,12- dimethylbenz(a)anthracene. Cancer Res 34(12):3229–3231PubMedGoogle Scholar
  25. 25.
    Boland GP, Butt IS, Prasad R, Knox WF, Bundred NJ (2004) COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ. Br J Cancer 90(2):423–429PubMedGoogle Scholar
  26. 26.
    Costa C, Soares R, Reis-Filho JS, Leitao D, Amendoeira I, Schmitt FC (2002) Cyclo-­oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer. J Clin Pathol 55(6):429–434PubMedGoogle Scholar
  27. 27.
    Davies G, Salter J, Hills M, Martin LA, Sacks N, Dowsett M (2003) Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer. Clin Cancer Res 9(7):2651–2656PubMedGoogle Scholar
  28. 28.
    Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, Kristiansen G, Reles A, Siegert A, Guski H, Hauptmann S (2003) Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 97(12):2978–2987PubMedGoogle Scholar
  29. 29.
    Half E, Tang XM, Gwyn K, Sahin A, Wathen K, Sinicrope FA (2002) Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res 62(6):1676–1681PubMedGoogle Scholar
  30. 30.
    Kelly LM, Hill AD, Kennedy S, Connolly EM, Ramanath R, Teh S, Dijkstra B, Purcell R, McDermott EW, O’Higgins N (2003) Lack of prognostic effect of Cox-2 expression in primary breast cancer on short-term follow-up. Eur J Surg Oncol 29(9):707–710PubMedGoogle Scholar
  31. 31.
    Lim SC (2003) Role of COX-2, VEGF and cyclin D1 in mammary infiltrating duct carcinoma. Oncol Rep 10(5):1241–1249PubMedGoogle Scholar
  32. 32.
    Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62(3):632–635PubMedGoogle Scholar
  33. 33.
    Shim JY, An HJ, Lee YH, Kim SK, Lee KP, Lee KS (2003) Overexpression of cyclooxygenase-­2 is associated with breast carcinoma and its poor prognostic factors. Mod Pathol 16(12):1199–1204PubMedGoogle Scholar
  34. 34.
    Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT (2000) COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89(12):2637–2645PubMedGoogle Scholar
  35. 35.
    Spizzo G, Gastl G, Wolf D, Gunsilius E, Steurer M, Fong D, Amberger A, Margreiter R, Obrist P (2003) Correlation of COX-2 and Ep-CAM overexpression in human invasive breast cancer and its impact on survival. Br J Cancer 88(4):574–578PubMedGoogle Scholar
  36. 36.
    Watanabe O, Shimizu T, Imamura H, Kinoshita J, Utada Y, Okabe T, Kimura K, Hirano A, Yoshimatsu K, Aiba M, Ogawa K (2003) Expression of cyclooxygenase-2 in malignant and benign breast tumors. Anticancer Res 23(4):3215–3221PubMedGoogle Scholar
  37. 37.
    Wulfing P, Diallo R, Muller C, Wulfing C, Poremba C, Heinecke A, Rody A, Greb RR, Bocker W, Kiesel L (2003) Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis. J Cancer Res Clin Oncol 129(7):375–382PubMedGoogle Scholar
  38. 38.
    Yoshimura N, Sano H, Okamoto M, Akioka K, Ushigome H, Kadotani Y, Yoshimura R, Nobori S, Higuchi A, Ohmori Y, Nakamura K (2003) Expression of cyclooxygenase-1 and -2 in human breast cancer. Surg Today 33(11):805–811PubMedGoogle Scholar
  39. 39.
    Shim V, Gauthier ML, Sudilovsky D, Mantei K, Chew KL, Moore DH, Cha I, Tlsty TD, Esserman LJ (2003) Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium. Cancer Res 63(10):2347–2350PubMedGoogle Scholar
  40. 40.
    Tan KB, Yong WP, Putti TC (2004) Cyclooxygenase-2 expression: a potential prognostic and predictive marker for high-grade ductal carcinoma in situ of the breast. Histopathology 44(1):24–28PubMedGoogle Scholar
  41. 41.
    Kirkpatrick K, Ogunkolade W, Elkak A, Bustin S, Jenkins P, Ghilchik M, Mokbel K (2002) The mRNA expression of cyclo-oxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in human breast cancer. Curr Med Res Opin 18(4):237–241PubMedGoogle Scholar
  42. 42.
    Crawford YG, Gauthier ML, Joubel A, Mantei K, Kozakiewicz K, Afshari CA, Tlsty TD (2004) Histologically normal human mammary epithelia with silenced p16(INK4a) overexpress COX-2, promoting a premalignant program. Cancer Cell 5(3):263–273PubMedGoogle Scholar
  43. 43.
    Yang WT, Lewis MT, Hess K, Wong H, Tsimelzon A, Karadag N, Cairo M, Wei C, Meric-­Bernstam F, Brown P, Arun B, Hortobagyi GN, Sahin A, Chang JC (2010) Decreased TGFbeta signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res Treat 119(2):305–314. doi: 10.1007/s10549-009-0350-0 PubMedGoogle Scholar
  44. 44.
    Holmes MD, Chen WY, Schnitt SJ, Collins L, Colditz GA, Hankinson SE, Tamimi RM (2011) COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin. Breast Cancer Res Treat 130(2):657–662. doi: 10.1007/s10549-011-1651-7 PubMedGoogle Scholar
  45. 45.
    Kerlikowske K, Molinaro AM, Gauthier ML, Berman HK, Waldman F, Bennington J, Sanchez H, Jimenez C, Stewart K, Chew K, Ljung BM, Tlsty TD (2010) Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Natl Cancer Inst 102(9):627–637. doi:djq101 [pii] 10.1093/jnci/djq101PubMedGoogle Scholar
  46. 46.
    Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ (2002) Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer. Evidence for involvement of AP-1 and PEA3. J Biol Chem 277:18649–18657PubMedGoogle Scholar
  47. 47.
    Badawi AF, el-Sohemy A, Stephen LL, Ghoshal AK, Archer MC (1999) Modulation of the expression of the cyclooxygenase 1 and 2 genes in rat mammary glands: role of hormonal status and dietary fat. Adv Exp Med Biol 469:119–124PubMedGoogle Scholar
  48. 48.
    Hamid R, Singh J, Reddy BS, Cohen LA (1999) Inhibition by dietary menhaden oil of cyclooxygenase-­1 and -2 in N-nitrosomethylurea-induced rat mammary tumors. Int J Oncol 14(3):523–528PubMedGoogle Scholar
  49. 49.
    Howe LR, Crawford HC, Subbaramaiah K, Hassell JA, Dannenberg AJ, Brown AMC (2001) PEA3 is upregulated in response to Wnt1 and activates the expression of cyclooxygenase-2. J Biol Chem 276(23):20108–20115PubMedGoogle Scholar
  50. 50.
    Howe LR, Subbaramaiah K, Patel J, Masferrer JL, Deora A, Hudis C, Thaler HT, Muller WJ, Du B, Brown AMC, Dannenberg AJ (2002) Celecoxib, a selective cyclooxygenase-2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 62:5405–5407PubMedGoogle Scholar
  51. 51.
    Nakatsugi S, Ohta T, Kawamori T, Mutoh M, Tanigawa T, Watanabe K, Sugie S, Sugimura T, Wakabayashi K (2000) Chemoprevention by nimesulide, a selective cyclooxygenase-2 inhibitor, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary gland carcinogenesis in rats. Jpn J Cancer Res 91(9):886–892PubMedGoogle Scholar
  52. 52.
    Robertson FM, Parrett ML, Joarder FS, Ross M, Abou-Issa HM, Alshafie G, Harris RE (1998) Ibuprofen-induced inhibition of cyclooxygenase isoform gene expression and regression of rat mammary carcinomas. Cancer Lett 122(1–2):165–175PubMedGoogle Scholar
  53. 53.
    Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hla T, Yang P, Kopelovich L, Hudis CA, Dannenberg AJ (2011) Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila) 4(3):329–346. doi:4/3/329 [pii] 10.1158/1940-6207.CAPR-10-0381Google Scholar
  54. 54.
    Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Giri D, Kopelovich L, Hudis CA, Dannenberg AJ (2012) Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov 2(4):356–365. doi:2159–8290.CD-11-0241 [pii] 10.1158/2159-8290.CD-11-0241PubMedGoogle Scholar
  55. 55.
    Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K (2005) Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54(8):2277–2286. doi:54/8/2277 [pii]PubMedGoogle Scholar
  56. 56.
    Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46(11):2347–2355. doi:M500294-JLR200 [pii] 10.1194/jlr.M500294-JLR200PubMedGoogle Scholar
  57. 57.
    Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S (2008) Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res 49(7):1562–1568. doi:M800019-JLR200 [pii] 10.1194/jlr.M800019-JLR200PubMedGoogle Scholar
  58. 58.
    Morris PG, Hudis CA, Giri D, Morrow M, Falcone DJ, Zhou XK, Du B, Brogi E, Crawford CB, Kopelovich L, Subbaramaiah K, Dannenberg AJ (2011) Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 4(7):1021–1029. doi:1940–6207.CAPR-11-0110 [pii] 10.1158/1940-6207.CAPR-11-0110Google Scholar
  59. 59.
    Sun X, Casbas-Hernandez P, Bigelow C, Makowski L, Joseph Jerry D, Smith Schneider S, Troester MA (2012) Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat 131(3):1003–1012. doi: 10.1007/s10549-011-1789-3 [doi]PubMedGoogle Scholar
  60. 60.
    Howe LR, Chang SH, Tolle KC, Dillon R, Young LJT, Cardiff RD, Newman RA, Yang P, Thaler HT, Muller WJ, Hudis C, Brown AMC, Hla T, Subbaramaiah K, Dannenberg AJ (2005) HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-­2 knockout mice. Cancer Res 65(21):10113–10119PubMedGoogle Scholar
  61. 61.
    Chulada PC, Thompson MB, Mahler JF, Doyle CM, Gaul BW, Lee C, Tiano HF, Morham SG, Smithies O, Langenbach R (2000) Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res 60(17):4705–4708PubMedGoogle Scholar
  62. 62.
    Tiano HF, Loftin CD, Akunda J, Lee CA, Spalding J, Sessoms A, Dunson DB, Rogan EG, Morham SG, Smart RC, Langenbach R (2002) Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res 62(12):3395–3401PubMedGoogle Scholar
  63. 63.
    Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hla T (2001) Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563–18569PubMedGoogle Scholar
  64. 64.
    Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC, Lane TF, Hla T (2004) Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci U S A 101(2):591–596PubMedGoogle Scholar
  65. 65.
    Muller-Decker K, Neufang G, Berger I, Neumann M, Marks F, Furstenberger G (2002) Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis. Proc Natl Acad Sci U S A 99(19):12483–12488PubMedGoogle Scholar
  66. 66.
    Wang D, Dubois RN (2006) Prostaglandins and cancer. Gut 55(1):115–122. doi:gut.2004.047100 [pii] 10.1136/gut.2004.047100PubMedGoogle Scholar
  67. 67.
    Nakanishi M, Montrose DC, Clark P, Nambiar PR, Belinsky GS, Claffey KP, Xu D, Rosenberg DW (2008) Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis. Cancer Res 68(9):3251–3259. doi:68/9/3251 [pii] 10.1158/0008-5472.CAN-07-6100PubMedGoogle Scholar
  68. 68.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:S0092-8674(11)00127-9 [pii] 10.1016/j.cell.2011.02.013PubMedGoogle Scholar
  69. 69.
    Bandyopadhyay GK, Imagawa W, Wallace D, Nandi S (1987) Linoleate metabolites enhance the in vitro proliferative response of mouse mammary epithelial cells to epidermal growth factor. J Biol Chem 262(6):2750–2756PubMedGoogle Scholar
  70. 70.
    Goin M, Pignataro O, Jimenez de Asua L (1993) Early cell cycle diacylglycerol (DAG) content and protein kinase C (PKC) activity enhancement potentiates prostaglandin F2 alpha (PGF2 alpha) induced mitogenesis in Swiss 3T3 cells. FEBS Lett 316(1):68–72PubMedGoogle Scholar
  71. 71.
    Nolan RD, Danilowicz RM, Eling TE (1988) Role of arachidonic acid metabolism in the mitogenic response of BALB/c 3T3 fibroblasts to epidermal growth factor. Mol Pharmacol 33(6):650–656PubMedGoogle Scholar
  72. 72.
    Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, Kaidi A (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30(3):377–386. doi:bgp014 [pii] 10.1093/carcin/bgp014PubMedGoogle Scholar
  73. 73.
    North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber GJ, Bowman TV, Jang IH, Grosser T, Fitzgerald GA, Daley GQ, Orkin SH, Zon LI (2007) Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447(7147):1007–1011. doi:nature05883 [pii] 10.1038/nature05883PubMedGoogle Scholar
  74. 74.
    Li HJ, Reinhardt F, Herschman HR, Weinberg RA (2012) Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov 2(9):840–855. doi:2159–8290.CD-12-0101 [pii] 10.1158/2159-8290.CD-12-0101PubMedGoogle Scholar
  75. 75.
    Rudnick JA, Arendt LM, Klebba I, Hinds JW, Iyer V, Gupta PB, Naber SP, Kuperwasser C (2011) Functional heterogeneity of breast fibroblasts is defined by a prostaglandin secretory phenotype that promotes expansion of cancer-stem like cells. PLoS One 6(9):e24605. doi:10.1371/journal.pone.0024605 PONE-D-11-11675 [pii]PubMedGoogle Scholar
  76. 76.
    Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS (2005) Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 310(5753):1504–1510. doi:1116221 [pii] 10.1126/science.1116221PubMedGoogle Scholar
  77. 77.
    Buchanan FG, Wang D, Bargiacchi F, DuBois RN (2003) Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 278(37):35451–35457. doi:10.1074/jbc.M302474200 M302474200 [pii]PubMedGoogle Scholar
  78. 78.
    Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS (2002) Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 8(3):289–293. doi:10.1038/nm0302-289 nm0302-289 [pii]PubMedGoogle Scholar
  79. 79.
    Ben-Baruch A (2006) Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. Semin Cancer Biol 16(1):38–52. doi:S1044-579X(05)00059-3 [pii] 10.1016/j.semcancer.2005.07.006PubMedGoogle Scholar
  80. 80.
    Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182(8):4499–4506. doi:182/8/4499 [pii] 10.4049/jimmunol.0802740PubMedGoogle Scholar
  81. 81.
    Chen EP, Smyth EM (2011) COX-2 and PGE2-dependent immunomodulation in breast cancer. Prostaglandins Other Lipid Mediat 96(1–4):14–20. doi:S1098-8823(11)00075-X [pii] 10.1016/j.prostaglandins.2011.08.005PubMedGoogle Scholar
  82. 82.
    Strassmann G, Patil-Koota V, Finkelman F, Fong M, Kambayashi T (1994) Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J Exp Med 180(6):2365–2370PubMedGoogle Scholar
  83. 83.
    Markosyan N, Chen EP, Ndong VN, Yao Y, Sterner CJ, Chodosh LA, Lawson JA, Fitzgerald GA, Smyth EM (2011) Deletion of cyclooxygenase 2 in mouse mammary epithelial cells delays breast cancer onset through augmentation of type 1 immune responses in tumors. Carcinogenesis 32(10):1441–1449. doi:bgr134 [pii] 10.1093/carcin/bgr134PubMedGoogle Scholar
  84. 84.
    Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22(1):33–40. doi:S1044-579X(11)00106-4 [pii] 10.1016/j.semcancer.2011.12.005PubMedGoogle Scholar
  85. 85.
    Sombroek CC, Stam AG, Masterson AJ, Lougheed SM, Schakel MJ, Meijer CJ, Pinedo HM, van den Eertwegh AJ, Scheper RJ, de Gruijl TD (2002) Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol 168(9):4333–4343PubMedGoogle Scholar
  86. 86.
    Stolina M, Sharma S, Zhu L, Dubinett SM (2000) Lung cancer cyclooxygenase-2 dependent inhibition of dendritic cells maturation and function. Proc Am Assoc Cancer Res 41:619Google Scholar
  87. 87.
    Tsujii M, DuBois RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83(3):493–501PubMedGoogle Scholar
  88. 88.
    Takahashi Y, Kawahara F, Noguchi M, Miwa K, Sato H, Seiki M, Inoue H, Tanabe T, Yoshimoto T (1999) Activation of matrix metalloproteinase-2 in human breast cancer cells overexpressing cyclooxygenase-1 or -2. FEBS Lett 460(1):145–148PubMedGoogle Scholar
  89. 89.
    Tsujii M, Kawano S, DuBois RN (1997) Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U S A 94(7):3336–3340PubMedGoogle Scholar
  90. 90.
    Connolly EM, Harmey JH, O’Grady T, Foley D, Roche-Nagle G, Kay E, Bouchier-Hayes DJ (2002) Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer. Br J Cancer 87(2):231–237PubMedGoogle Scholar
  91. 91.
    Kundu N, Fulton AM (2002) Selective cyclooxygenase (COX)-1 or COX-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res 62(8):2343–2346PubMedGoogle Scholar
  92. 92.
    Roche-Nagle G, Connolly EM, Eng M, Bouchier-Hayes DJ, Harmey JH (2004) Antimetastatic activity of a cyclooxygenase-2 inhibitor. Br J Cancer 91(2):359–365PubMedGoogle Scholar
  93. 93.
    Miyaura C, Inada M, Suzawa T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, Suda T (2000) Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-­knockout mice. J Biol Chem 275(26):19819–19823PubMedGoogle Scholar
  94. 94.
    Okada Y, Lorenzo JA, Freeman AM, Tomita M, Morham SG, Raisz LG, Pilbeam CC (2000) Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture. J Clin Invest 105(6):823–832PubMedGoogle Scholar
  95. 95.
    Ono K, Akatsu T, Murakami T, Nishikawa M, Yamamoto M, Kugai N, Motoyoshi K, Nagata N (1998) Important role of EP4, a subtype of prostaglandin (PG) E receptor, in osteoclast-like cell formation from mouse bone marrow cells induced by PGE2. J Endocrinol 158(3):R1–R5PubMedGoogle Scholar
  96. 96.
    Sabino MA, Ghilardi JR, Jongen JL, Keyser CP, Luger NM, Mach DB, Peters CM, Rogers SD, Schwei MJ, de Felipe C, Mantyh PW (2002) Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Res 62(24):7343–7349PubMedGoogle Scholar
  97. 97.
    Powles TJ, Dowsett M, Easty GC, Easty DM, Neville AM (1976) Breast-cancer osteolysis, bone metastases, and anti-osteolytic effect of aspirin. Lancet 1(7960):608–610. doi:S0140-­6736(76)90416-5 [pii]PubMedGoogle Scholar
  98. 98.
    Seno H, Oshima M, Ishikawa TO, Oshima H, Takaku K, Chiba T, Narumiya S, Taketo MM (2002) Cyclooxygenase 2- and prostaglandin E2 receptor EP2-dependent angiogenesis in Apc∆716 mouse intestinal polyps. Cancer Res 62(2):506–511PubMedGoogle Scholar
  99. 99.
    Takeda H, Sonoshita M, Oshima H, Sugihara K, Chulada PC, Langenbach R, Oshima M, Taketo MM (2003) Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis. Cancer Res 63(16):4872–4877PubMedGoogle Scholar
  100. 100.
    Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN (2000) Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 105(11):1589–1594PubMedGoogle Scholar
  101. 101.
    Peterson HI (1983) Effects of prostaglandin synthesis inhibitors on tumor growth and vascularization. Experimental studies in the rat. Invasion Metastasis 3(3):151–159PubMedGoogle Scholar
  102. 102.
    Daniel TO, Liu H, Morrow JD, Crews BC, Marnett LJ (1999) Thromboxane A2 is a mediator of cyclooxygenase-2-dependent endothelial migration and angiogenesis. Cancer Res 59(18):4574–4577PubMedGoogle Scholar
  103. 103.
    Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL (2002) Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 62(3):625–631PubMedGoogle Scholar
  104. 104.
    Majima M, Isono M, Ikeda Y, Hayashi I, Hatanaka K, Harada Y, Katsumata O, Yamashina S, Katori M, Yamamoto S (1997) Significant roles of inducible cyclooxygenase (COX)-2 in angiogenesis in rat sponge implants. Jpn J Pharmacol 75(2):105–114PubMedGoogle Scholar
  105. 105.
    Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K (2000) Antiangiogenic and antitumor activities of cyclooxygenase-­2 inhibitors. Cancer Res 60(5):1306–1311PubMedGoogle Scholar
  106. 106.
    Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Sasaki Y, Kawano S, Hori M (1999) Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest 79(12):1469–1477PubMedGoogle Scholar
  107. 107.
    Yamada M, Kawai M, Kawai Y, Mashima Y (1999) The effect of selective cyclooxygenase-2 inhibitor on corneal angiogenesis in the rat. Curr Eye Res 19(4):300–304PubMedGoogle Scholar
  108. 108.
    Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, Tarnawski AS (1999) Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5(12):1418–1423PubMedGoogle Scholar
  109. 109.
    Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93(5):705–716. doi:S0092-­8674(00)81433-6 [pii]PubMedGoogle Scholar
  110. 110.
    Gately S, Li WW (2004) Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31(2 suppl 7):2–11PubMedGoogle Scholar
  111. 111.
    Leahy KM, Koki AT, Masferrer JL (2000) Role of cyclooxygenases in angiogenesis. Curr Med Chem 7(11):1163–1170PubMedGoogle Scholar
  112. 112.
    Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Saito Y (2003) Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia 46(11):1483–1488PubMedGoogle Scholar
  113. 113.
    Garcia de la Torre N, Rubio MA, Bordiu E, Cabrerizo L, Aparicio E, Hernandez C, Sanchez-­Pernaute A, Diez-Valladares L, Torres AJ, Puente M, Charro AL (2008) Effects of weight loss after bariatric surgery for morbid obesity on vascular endothelial growth factor-A, adipocytokines, and insulin. J Clin Endocrinol Metab 93(11):4276–4281. doi:jc.2007-1370 [pii] 10.1210/jc.2007-1370PubMedGoogle Scholar
  114. 114.
    Silha JV, Krsek M, Sucharda P, Murphy LJ (2005) Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond) 29(11):1308–1314. doi:0802987 [pii] 10.1038/sj.ijo.0802987Google Scholar
  115. 115.
    Gu JW, Young E, Patterson SG, Makey KL, Wells J, Huang M, Tucker KB, Miele L (2011) Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice. Cancer Biol Ther 11(10):910–917. doi:15473 [pii]PubMedGoogle Scholar
  116. 116.
    Chen CT, Du Y, Yamaguchi H, Hsu JM, Kuo HP, Hortobagyi GN, Hung MC (2012) Targeting the IKKbeta/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-­related breast cancer. Mol Cancer Ther 11(10):2212–2221. doi:1535–7163.MCT-12-0180 [pii] 10.1158/1535-7163.MCT-12-0180PubMedGoogle Scholar
  117. 117.
    Barnes NL, Warnberg F, Farnie G, White D, Jiang W, Anderson E, Bundred NJ (2007) Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer. Br J Cancer 96(4):575–582. doi:6603593 [pii] 10.1038/sj.bjc.6603593PubMedGoogle Scholar
  118. 118.
    Timoshenko AV, Chakraborty C, Wagner GF, Lala PK (2006) COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer 94(8):1154–1163. doi:6603593 [pii] 10.1038/sj.bjc.6603593PubMedGoogle Scholar
  119. 119.
    Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, Speed C, Jones M (2002) Aromatase—a brief overview. Annu Rev Physiol 64:93–127. doi:10.1146/annurev.physiol.64.081601.142703 64/1/93 [pii]PubMedGoogle Scholar
  120. 120.
    Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER (1993) A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 77(6):1622–1628PubMedGoogle Scholar
  121. 121.
    Lipton A, Santen RJ, Santner SJ, Harvey HA, Sanders SI, Matthews YL (1992) Prognostic value of breast cancer aromatase. Cancer 70(7):1951–1955PubMedGoogle Scholar
  122. 122.
    Miller WR, Anderson TJ, Jack WJ (1990) Relationship between tumour aromatase activity, tumour characteristics and response to therapy. J Steroid Biochem Mol Biol 37(6):1055–1059PubMedGoogle Scholar
  123. 123.
    Silva MC, Rowlands MG, Dowsett M, Gusterson B, McKinna JA, Fryatt I, Coombes RC (1989) Intratumoral aromatase as a prognostic factor in human breast carcinoma. Cancer Res 49(10):2588–2591PubMedGoogle Scholar
  124. 124.
    Agarwal VR, Bulun SE, Leitch M, Rohrich R, Simpson ER (1996) Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients. J Clin Endocrinol Metab 81(11):3843–3849PubMedGoogle Scholar
  125. 125.
    Chen S, Itoh T, Wu K, Zhou D, Yang C (2002) Transcriptional regulation of aromatase expression in human breast tissue. J Steroid Biochem Mol Biol 83(1–5):93–99PubMedGoogle Scholar
  126. 126.
    Mahendroo MS, Mendelson CR, Simpson ER (1993) Tissue-specific and hormonally controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue. J Biol Chem 268(26):19463–19470PubMedGoogle Scholar
  127. 127.
    Zhou D, Chen S (1999) Identification and characterization of a cAMP-responsive element in the region upstream from promoter 1.3 of the human aromatase gene. Arch Biochem Biophys 371(2):179–190PubMedGoogle Scholar
  128. 128.
    Narumiya S, Sugimoto Y, Ushikubi F (1999) Prostanoid receptors: structures, properties, and functions. Physiol Rev 79(4):1193–1226PubMedGoogle Scholar
  129. 129.
    Brueggemeier RW, Richards JA, Joomprabutra S, Bhat AS, Whetstone JL (2001) Molecular pharmacology of aromatase and its regulation by endogenous and exogenous agents. J Steroid Biochem Mol Biol 79(1–5):75–84PubMedGoogle Scholar
  130. 130.
    Singh A, Purohit A, Ghilchik MW, Reed MJ (1999) The regulation of aromatase activity in breast fibroblasts: the role of interleukin-6 and prostaglandin E2. Endocr Relat Cancer 6(2):139–147PubMedGoogle Scholar
  131. 131.
    Zhao Y, Agarwal VR, Mendelson CR, Simpson ER (1996) Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. Endocrinology 137(12):5739–5742PubMedGoogle Scholar
  132. 132.
    Subbaramaiah K, Hudis C, Chang SH, Hla T, Dannenberg AJ (2008) EP2 and EP4 receptors regulate aromatase expression in human adipocytes and breast cancer cells. Evidence of a BRCA1 and p300 exchange. J Biol Chem 283(6):3433–3444. doi:M705409200 [pii] ­10.1074/jbc.M705409200PubMedGoogle Scholar
  133. 133.
    Prosperi JR, Robertson FM (2006) Cyclooxygenase-2 directly regulates gene expression of P450 Cyp19 aromatase promoter regions pII, pI.3 and pI.7 and estradiol production in human breast tumor cells. Prostaglandins Other Lipid Mediat 81(1–2):55–70. doi:S1098-­8823(06)00115-8 [pii] 10.1016/j.prostaglandins.2006.07.003PubMedGoogle Scholar
  134. 134.
    Brodie AM, Lu Q, Long BJ, Fulton A, Chen T, Macpherson N, DeJong PC, Blankenstein MA, Nortier JW, Slee PH, van de Ven J, van Gorp JM, Elbers JR, Schipper ME, Blijham GH, Thijssen JH (2001) Aromatase and COX-2 expression in human breast cancers. J Steroid Biochem Mol Biol 79(1–5):41–47PubMedGoogle Scholar
  135. 135.
    Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, Robertson FM (1999) Correlation of aromatase and cyclooxygenase gene expression in human breast cancer ­specimens. Cancer Lett 140(1–2):27–35PubMedGoogle Scholar
  136. 136.
    Salhab M, Singh-Ranger G, Mokbel R, Jouhra F, Jiang WG, Mokbel K (2007) Cyclooxygenase-2 mRNA expression correlates with aromatase expression in human breast cancer. J Surg Oncol 96(5):424–428. doi: 10.1002/jso.20740 PubMedGoogle Scholar
  137. 137.
    Subbaramaiah K, Howe LR, Port ER, Brogi E, Fishman J, Liu CH, Hla T, Hudis C, Dannenberg AJ (2006) HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res 66(10):5504–5511. doi:66/10/5504 [pii] 10.1158/0008-5472.CAN-05-4076PubMedGoogle Scholar
  138. 138.
    Gates MA, Tworoger SS, Eliassen AH, Missmer SA, Hankinson SE (2010) Analgesic use and sex steroid hormone concentrations in postmenopausal women. Cancer Epidemiol Biomarkers Prev 19(4):1033–1041. doi:1055–9965.EPI-09-0975 [pii] 10.1158/1055-9965.EPI-09-0975PubMedGoogle Scholar
  139. 139.
    Hudson AG, Gierach GL, Modugno F, Simpson J, Wilson JW, Evans RW, Vogel VG, Weissfeld JL (2008) Nonsteroidal anti-inflammatory drug use and serum total estradiol in postmenopausal women. Cancer Epidemiol Biomarkers Prev 17(3):680–687. doi:17/3/680 [pii] 10.1158/1055-9965.EPI-07-2739PubMedGoogle Scholar
  140. 140.
    Cauley JA, Gutai JP, Kuller LH, LeDonne D, Powell JG (1989) The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol 129(6):1120–1131PubMedGoogle Scholar
  141. 141.
    Kaye SA, Folsom AR, Soler JT, Prineas RJ, Potter JD (1991) Associations of body mass and fat distribution with sex hormone concentrations in postmenopausal women. Int J Epidemiol 20(1):151–156PubMedGoogle Scholar
  142. 142.
    McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R, Gilliland F, Stanczyk FZ, Yasui Y, Ballard-Barbash R (2003) Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 21(10):1961–1966. doi:10.1200/JCO.2003.07.057 JCO.2003.07.057 [pii]PubMedGoogle Scholar
  143. 143.
    Wake DJ, Strand M, Rask E, Westerbacka J, Livingstone DE, Soderberg S, Andrew R, Yki-­Jarvinen H, Olsson T, Walker BR (2007) Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol (Oxf) 66(3):440–446. doi:CEN2755 [pii] 10.1111/j.1365-2265.2007.02755.xGoogle Scholar
  144. 144.
    Marnett LJ (1992) Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52(20):5575–5589PubMedGoogle Scholar
  145. 145.
    Corpet DE, Pierre F (2003) Point: from animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol Biomarkers Prev 12(5):391–400PubMedGoogle Scholar
  146. 146.
    Rao CV, Reddy BS (2004) NSAIDs and chemoprevention. Curr Cancer Drug Targets 4(1):29–42PubMedGoogle Scholar
  147. 147.
    Howe LR (2005) Cyclooxygenase-2 and breast cancer. In: Yao AP (ed) Trends in breast cancer research, vol 9, Horizons in cancer research. Nova, New York, pp 1–38Google Scholar
  148. 148.
    Buchanan FG, Holla V, Katkuri S, Matta P, DuBois RN (2007) Targeting cyclooxygenase-2 and the epidermal growth factor receptor for the prevention and treatment of intestinal cancer. Cancer Res 67(19):9380–9388. doi:67/19/9380 [pii] 10.1158/0008-5472.CAN-07-0710PubMedGoogle Scholar
  149. 149.
    Torrance CJ, Jackson PE, Montgomery E, Kinzler KW, Vogelstein B, Wissner A, Nunes M, Frost P, Discafani CM (2000) Combinatorial chemoprevention of intestinal neoplasia. Nat Med 6(9):1024–1028. doi: 10.1038/79534 PubMedGoogle Scholar
  150. 150.
    Mann M, Sheng H, Shao J, Williams CS, Pisacane PI, Sliwkowski MX, DuBois RN (2001) Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology 120(7):1713–1719PubMedGoogle Scholar
  151. 151.
    Reddy BS, Patlolla JM, Simi B, Wang SH, Rao CV (2005) Prevention of colon cancer by low doses of celecoxib, a cyclooxygenase inhibitor, administered in diet rich in omega-3 polyunsaturated fatty acids. Cancer Res 65(17):8022–8027. doi:65/17/8022 [pii] 10.1158/0008-­5472.CAN-05-0212PubMedGoogle Scholar
  152. 152.
    Reddy BS, Wang CX, Kong AN, Khor TO, Zheng X, Steele VE, Kopelovich L, Rao CV (2006) Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats. Cancer Res 66(8):4542–4546. doi:66/8/4542 [pii] 10.1158/0008-5472.CAN-05-4428PubMedGoogle Scholar
  153. 153.
    Swamy MV, Patlolla JM, Steele VE, Kopelovich L, Reddy BS, Rao CV (2006) Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APCMin mice. Cancer Res 66(14):7370–7377. doi:66/14/7370 [pii] 10.1158/0008-5472.CAN-05-4619PubMedGoogle Scholar
  154. 154.
    Ignatenko NA, Besselsen DG, Stringer DE, Blohm-Mangone KA, Cui H, Gerner EW (2008) Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis. Nutr Cancer 60(suppl 1):30–35. doi:905311576 [pii] 10.1080/01635580802401317PubMedGoogle Scholar
  155. 155.
    Lanza-Jacoby S, Miller S, Flynn J, Gallatig K, Daskalakis C, Masferrer JL, Zweifel BS, Sembhi H, Russo IH (2003) The cyclooxygenase-2 inhibitor, celecoxib, prevents the development of mammary tumors in Her-2/neu mice. Cancer Epidemiol Biomarkers Prev 12(12):1486–1491PubMedGoogle Scholar
  156. 156.
    Woditschka S, Haag JD, Mau B, Lubet RA, Gould MN (2008) Chemopreventive effects of celecoxib are limited to hormonally responsive mammary carcinomas in the neu-induced retroviral rat model. Breast Cancer Res 10(1):R18. doi:bcr1864 [pii] 10.1186/bcr1864PubMedGoogle Scholar
  157. 157.
    Brown PH, Subbaramaiah K, Salmon AP, Baker R, Newman RA, Yang P, Zhou XK, Bissonnette RP, Dannenberg AJ, Howe LR (2008) Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-­selective retinoid. Cancer Prev Res (Phila) 1(3):208–214. doi:1/3/208 [pii] 10.1158/1940-­6207.CAPR-08-0021Google Scholar
  158. 158.
    Chan AT, Arber N, Burn J, Chia WK, Elwood P, Hull MA, Logan RF, Rothwell PM, Schror K, Baron JA (2012) Aspirin in the chemoprevention of colorectal neoplasia: an overview. Cancer Prev Res (Phila) 5(2):164–178. doi:1940–6207.CAPR-11-0391 [pii] 10.1158/1940-­6207.CAPR-11-0391Google Scholar
  159. 159.
    Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C (2012) Aspirin and cancer risk: a quantitative review to 2011. Ann Oncol 23(6):1403–1415. doi:mds113 [pii] 10.1093/annonc/mds113PubMedGoogle Scholar
  160. 160.
    Reeves MJ, Newcomb PA, Trentham-Dietz A, Storer BE, Remington PL (1996) Nonsteroidal anti-inflammatory drug use and protection against colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 5(12):955–960PubMedGoogle Scholar
  161. 161.
    Rosenberg L, Louik C, Shapiro S (1998) Nonsteroidal antiinflammatory drug use and reduced risk of large bowel carcinoma. Cancer 82(12):2326–2333. doi:10.1002/(SICI)1097-­0142(19980615)82:12<2326::AID-CNCR5>3.0.CO;2-Q [pii]PubMedGoogle Scholar
  162. 162.
    Harris RE, Beebe-Donk J, Alshafie GA (2008) Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 8:237. doi:1471-2407-8-237 [pii] 10.1186/1471-2407-8-237PubMedGoogle Scholar
  163. 163.
    Ruder EH, Laiyemo AO, Graubard BI, Hollenbeck AR, Schatzkin A, Cross AJ (2011) Non-­steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol 106(7):1340–1350. doi:ajg201138 [pii] 10.1038/ajg.2011.38PubMedGoogle Scholar
  164. 164.
    Rahme E, Barkun AN, Toubouti Y, Bardou M (2003) The cyclooxygenase-2-selective inhibitors rofecoxib and celecoxib prevent colorectal neoplasia occurrence and recurrence. Gastroenterology 125(2):404–412. doi:S0016508503008801 [pii]PubMedGoogle Scholar
  165. 165.
    Vinogradova Y, Hippisley-Cox J, Coupland C, Logan RF (2007) Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case–control study. Gastroenterology 133(2):393–402. doi:S0016-­5085(07)01005-0 [pii] 10.1053/j.gastro.2007.05.023PubMedGoogle Scholar
  166. 166.
    Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377(9759):31–41. doi:S0140-6736(10)62110-1 [pii] 10.1016/S0140-6736(10)62110-1PubMedGoogle Scholar
  167. 167.
    Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376(9754):1741–1750. doi:S0140-6736(10)61543-7 [pii] 10.1016/S0140-6736(10)61543-7PubMedGoogle Scholar
  168. 168.
    Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z (2012) Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379(9826):1591–1601. doi:S0140-6736(12)60209-8 [pii] 10.1016/S0140-6736(12)60209-8PubMedGoogle Scholar
  169. 169.
    Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJ (1993) Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328(18):1313–1316PubMedGoogle Scholar
  170. 170.
    Giardiello FM, Spannhake EW, DuBois RN, Hylind LM, Robinson CR, Hubbard WC, Hamilton SR, Yang VW (1998) Prostaglandin levels in human colorectal mucosa: effects of sulindac in patients with familial adenomatous polyposis. Dig Dis Sci 43(2):311–316PubMedGoogle Scholar
  171. 171.
    Meyskens FL Jr, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, Kelloff G, Lawson MJ, Kidao J, McCracken J, Albers CG, Ahnen DJ, Turgeon DK, Goldschmid S, Lance P, Hagedorn CH, Gillen DL, Gerner EW (2008) Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-­blind trial. Cancer Prev Res (Phila) 1(1):32–38. doi: 10.1158/1940-6207.CAPR-08-0042 Google Scholar
  172. 172.
    Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU (2003) A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 348(10):891–899PubMedGoogle Scholar
  173. 173.
    Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR (2008) Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 134(1):29–38. doi:S0016-5085(07)01813-6 [pii] 10.1053/j.gastro.2007.10.014PubMedGoogle Scholar
  174. 174.
    Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G, Schilsky R (2003) A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348(10):883–890PubMedGoogle Scholar
  175. 175.
    Benamouzig R, Deyra J, Martin A, Girard B, Jullian E, Piednoir B, Couturier D, Coste T, Little J, Chaussade S (2003) Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology 125(2):328–336. doi:S0016508503008874 [pii]PubMedGoogle Scholar
  176. 176.
    Cole BF, Logan RF, Halabi S, Benamouzig R, Sandler RS, Grainge MJ, Chaussade S, Baron JA (2009) Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst 101(4):256–266. doi:djn485 [pii] 10.1093/jnci/djn485PubMedGoogle Scholar
  177. 177.
    Benamouzig R, Uzzan B, Deyra J, Martin A, Girard B, Little J, Chaussade S (2012) Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial. Gut 61(2):255–261. doi:gutjnl-2011-300113 [pii] 10.1136/gutjnl-2011-300113PubMedGoogle Scholar
  178. 178.
    Barnes CJ, Hamby-Mason RL, Hardman WE, Cameron IL, Speeg KV, Lee M (1999) Effect of aspirin on prostaglandin E2 formation and transforming growth factor alpha expression in human rectal mucosa from individuals with a history of adenomatous polyps of the colon. Cancer Epidemiol Biomarkers Prev 8(4 pt 1):311–315PubMedGoogle Scholar
  179. 179.
    Frommel TO, Dyavanapalli M, Oldham T, Kazi N, Lietz H, Liao Y, Mobarhan S (1997) Effect of aspirin on prostaglandin E2 and leukotriene B4 production in human colonic mucosa from cancer patients. Clin Cancer Res 3(2):209–213PubMedGoogle Scholar
  180. 180.
    Krishnan K, Ruffin MT, Normolle D, Shureiqi I, Burney K, Bailey J, Peters-Golden M, Rock CL, Boland CR, Brenner DE (2001) Colonic mucosal prostaglandin E2 and cyclooxygenase expression before and after low aspirin doses in subjects at high risk or at normal risk for colorectal cancer. Cancer Epidemiol Biomarkers Prev 10(5):447–453PubMedGoogle Scholar
  181. 181.
    Ruffin MT, Krishnan K, Rock CL, Normolle D, Vaerten MA, Peters-Golden M, Crowell J, Kelloff G, Boland CR, Brenner DE (1997) Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose. J Natl Cancer Inst 89(15):1152–1160PubMedGoogle Scholar
  182. 182.
    Sample D, Wargovich M, Fischer SM, Inamdar N, Schwartz P, Wang X, Do KA, Sinicrope FA (2002) A dose-finding study of aspirin for chemoprevention utilizing rectal mucosal prostaglandin E(2) levels as a biomarker. Cancer Epidemiol Biomarkers Prev 11(3):275–279PubMedGoogle Scholar
  183. 183.
    Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJ, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop DT (2011) Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378(9809):2081–2087. doi:S0140-6736(11)61049-0 [pii] 10.1016/S0140-6736(11)61049-0PubMedGoogle Scholar
  184. 184.
    Sturmer T, Glynn RJ, Lee IM, Manson JE, Buring JE, Hennekens CH (1998) Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians’ Health Study. Ann Intern Med 128(9):713–720PubMedGoogle Scholar
  185. 185.
    Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE (2005) Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA 294(1):47–55. doi:294/1/47 [pii] 10.1001/jama.294.1.47PubMedGoogle Scholar
  186. 186.
    Dube C, Rostom A, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D (2007) The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med 146(5):365–375. doi:146/5/365 [pii]PubMedGoogle Scholar
  187. 187.
    Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, Jankowski J, La Vecchia C, Meyskens F, Senn HJ, Thun M (2009) Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 10(5):501–507. doi:S1470-2045(09)70035-X [pii] 10.1016/S1470-2045(09)70035-XPubMedGoogle Scholar
  188. 188.
    Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS (2005) Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294(8):914–923. doi:294/8/914 [pii] 10.1001/jama.294.8.914PubMedGoogle Scholar
  189. 189.
    Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Wu K, Fuchs CS (2008) Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology 134(1):21–28. doi:S0016-5085(07)01745-3 [pii] 10.1053/j.gastro.2007.09.035PubMedGoogle Scholar
  190. 190.
    Chan AT, Manson JE, Feskanich D, Stampfer MJ, Colditz GA, Fuchs CS (2007) Long-term aspirin use and mortality in women. Arch Intern Med 167(6):562–572. doi:167/6/562 [pii] 10.1001/archinte.167.6.562PubMedGoogle Scholar
  191. 191.
    Coghill AE, Newcomb PA, Chia VM, Zheng Y, Wernli KJ, Passarelli MN, Potter JD (2011) Pre-diagnostic NSAID use but not hormone therapy is associated with improved colorectal cancer survival in women. Br J Cancer 104(5):763–768. doi:6606041 [pii] 10.1038/sj.bjc.6606041PubMedGoogle Scholar
  192. 192.
    Zell JA, Ziogas A, Bernstein L, Clarke CA, Deapen D, Largent JA, Neuhausen SL, Stram DO, Ursin G, Anton-Culver H (2009) Nonsteroidal anti-inflammatory drugs: effects on mortality after colorectal cancer diagnosis. Cancer 115(24):5662–5671. doi: 10.1002/cncr.24705 PubMedGoogle Scholar
  193. 193.
    Din FV, Theodoratou E, Farrington SM, Tenesa A, Barnetson RA, Cetnarskyj R, Stark L, Porteous ME, Campbell H, Dunlop MG (2010) Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut 59(12):1670–1679. doi:gut.2009.203000 [pii] 10.1136/gut.2009.203000PubMedGoogle Scholar
  194. 194.
    Chan AT, Ogino S, Fuchs CS (2009) Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302(6):649–658. doi:302/6/649 [pii] 10.1001/jama.2009.1112PubMedGoogle Scholar
  195. 195.
    Bastiaannet E, Sampieri K, Dekkers OM, de Craen AJ, van Herk-Sukel MP, Lemmens V, van den Broek CB, Coebergh JW, Herings RM, van de Velde CJ, Fodde R, Liefers GJ (2012) Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 106(9):1564–1570. doi:bjc2012101 [pii] 10.1038/bjc.2012.101PubMedGoogle Scholar
  196. 196.
    Walker AJ, Grainge MJ, Card TR (2012) Aspirin and other non-steroidal anti-inflammatory drug use and colorectal cancer survival: a cohort study. Br J Cancer 107(9):1602–1607. doi:bjc2012427 [pii] 10.1038/bjc.2012.427PubMedGoogle Scholar
  197. 197.
    Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356(21):2131–2142. doi:356/21/2131 [pii] 10.1056/NEJMoa067208PubMedGoogle Scholar
  198. 198.
    Benamouzig R, Uzzan B, Martin A, Deyra J, Little J, Girard B, Chaussade S (2010) Cyclooxygenase-2 expression and recurrence of colorectal adenomas: effect of aspirin chemoprevention. Gut 59(5):622–629. doi:59/5/622 [pii] 10.1136/gut.2008.175406PubMedGoogle Scholar
  199. 199.
    Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA, Giovannucci E, Fuchs CS, Chan AT, Ogino S (2012) Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367(17):1596–1606. doi: 10.1056/NEJMoa1207756 PubMedGoogle Scholar
  200. 200.
    Johnson CC, Hayes RB, Schoen RE, Gunter MJ, Huang WY (2010) Non-steroidal anti-­inflammatory drug use and colorectal polyps in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Gastroenterol 105(12):2646–2655. doi:ajg2010349 [pii] 10.1038/ajg.2010.349PubMedGoogle Scholar
  201. 201.
    Zhang X, Smith-Warner SA, Chan AT, Wu K, Spiegelman D, Fuchs CS, Willett WC, Giovannucci EL (2011) Aspirin use, body mass index, physical activity, plasma C-peptide, and colon cancer risk in US health professionals. Am J Epidemiol 174(4):459–467. doi:kwr115 [pii] 10.1093/aje/kwr115PubMedGoogle Scholar
  202. 202.
    Kim S, Baron JA, Mott LA, Burke CA, Church TR, McKeown-Eyssen GE, Cole BF, Haile RW, Sandler RS (2006) Aspirin may be more effective in preventing colorectal adenomas in patients with higher BMI (United States). Cancer Causes Control 17(10):1299–1304. doi: 10.1007/s10552-006-0075-x PubMedGoogle Scholar
  203. 203.
    Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B (2000) The effect of celecoxib, a cyclooxygenase-­2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342(26):1946–1952PubMedGoogle Scholar
  204. 204.
    Arber N, Eagle CJ, Spicak J, Racz I, Dite P, Hajer J, Zavoral M, Lechuga MJ, Gerletti P, Tang J, Rosenstein RB, Macdonald K, Bhadra P, Fowler R, Wittes J, Zauber AG, Solomon SD, Levin B (2006) Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355(9):885–895. doi:355/9/885 [pii] 10.1056/NEJMoa061652PubMedGoogle Scholar
  205. 205.
    Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A, Bolognese JA, Oxenius B, Horgan K, Loftus S, Morton DG (2006) A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 131(6):1674–1682. doi:S0016-­5085(06)01994-9 [pii] 10.1053/j.gastro.2006.08.079PubMedGoogle Scholar
  206. 206.
    Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355(9):873–884PubMedGoogle Scholar
  207. 207.
    Yan M, Myung SJ, Fink SP, Lawrence E, Lutterbaugh J, Yang P, Zhou X, Liu D, Rerko RM, Willis J, Dawson D, Tai HH, Barnholtz-Sloan JS, Newman RA, Bertagnolli MM, Markowitz SD (2009) 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. Proc Natl Acad Sci U S A 106(23):9409–9413. doi:0902367106 [pii] 10.1073/pnas.0902367106PubMedGoogle Scholar
  208. 208.
    Tai HH, Chi X, Tong M (2011) Regulation of 15-hydroxyprostaglandin dehydrogenase (15-­PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins Other Lipid Mediat 96(1–4):37–40. doi:S1098-8823(11)00045-1 [pii] 10.1016/j.prostaglandins.2011.06.005PubMedGoogle Scholar
  209. 209.
    Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL (2008) Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 372(9651):1756–1764. doi:S0140-6736(08)61490-7 [pii] 10.1016/S0140-6736(08)61490-7PubMedGoogle Scholar
  210. 210.
    Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352(11):1092–1102. doi:NEJMoa050493 [pii] 10.1056/NEJMoa050493PubMedGoogle Scholar
  211. 211.
    Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352(11):1071–1080. doi:NEJMoa050405 [pii] 10.1056/NEJMoa050405PubMedGoogle Scholar
  212. 212.
    Solomon SD, Pfeffer MA, McMurray JJ, Fowler R, Finn P, Levin B, Eagle C, Hawk E, Lechuga M, Zauber AG, Bertagnolli MM, Arber N, Wittes J (2006) Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 114(10):1028–1035. doi:CIRCULATIONAHA.106.636746 [pii] 10.1161/CIRCULATIONAHA.106.636746PubMedGoogle Scholar
  213. 213.
    Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RS, Stanley A, Stokes JC, Julier P, Iveson C, Duvvuri R, McConkey CC (2007) Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 357(4):360–369. doi:357/4/360 [pii] 10.1056/NEJMoa071841PubMedGoogle Scholar
  214. 214.
    Rostom A, Dube C, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D (2007) Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med 146(5):376–389. doi:146/5/376 [pii]PubMedGoogle Scholar
  215. 215.
    Chan AT, Sima CS, Zauber AG, Ridker PM, Hawk ET, Bertagnolli MM (2011) C-reactive protein and risk of colorectal adenoma according to celecoxib treatment. Cancer Prev Res (Phila) 4(8):1172–1180. doi:4/8/1172 [pii] 10.1158/1940-6207.CAPR-10-0403Google Scholar
  216. 216.
    Luo T, Yan HM, He P, Luo Y, Yang YF, Zheng H (2012) Aspirin use and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 131(2):581–587. doi: 10.1007/s10549-011-1747-0 PubMedGoogle Scholar
  217. 217.
    Takkouche B, Regueira-Mendez C, Etminan M (2008) Breast cancer and use of nonsteroidal anti-inflammatory drugs: a meta-analysis. J Natl Cancer Inst 100(20):1439–1447. doi:djn324 [pii] 10.1093/jnci/djn324PubMedGoogle Scholar
  218. 218.
    Ashok V, Dash C, Rohan TE, Sprafka JM, Terry PD (2011) Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. Breast 20(1):66–70. doi:S0960-9776(10)00176-1 [pii] 10.1016/j.breast.2010.07.004PubMedGoogle Scholar
  219. 219.
    Brasky TM, Bonner MR, Moysich KB, Ambrosone CB, Nie J, Tao MH, Edge SB, Kallakury BV, Marian C, Trevisan M, Shields PG, Freudenheim JL (2010) Non-steroidal anti-­inflammatory drug (NSAID) use and breast cancer risk in the Western New York Exposures and Breast Cancer (WEB) Study. Cancer Causes Control 21(9):1503–1512. doi: 10.1007/s10552-010-9579-5 PubMedGoogle Scholar
  220. 220.
    Harris RE, Beebe-Donk J, Alshafie GA (2006) Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 6:27. doi:1471-2407-6-27 [pii] 10.1186/1471-2407-6-27PubMedGoogle Scholar
  221. 221.
    Harris RE, Chlebowski RT, Jackson RD, Frid DJ, Ascenseo JL, Anderson G, Loar A, Rodabough RJ, White E, McTiernan A (2003) Breast cancer and nonsteroidal ­anti-­inflammatory drugs: prospective results from the Women’s Health Initiative. Cancer Res 63(18):6096–6101PubMedGoogle Scholar
  222. 222.
    Terry MB, Gammon MD, Zhang FF, Tawfik H, Teitelbaum SL, Britton JA, Subbaramaiah K, Dannenberg AJ, Neugut AI (2004) Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291(20):2433–2440PubMedGoogle Scholar
  223. 223.
    Bosco JL, Palmer JR, Boggs DA, Hatch EE, Rosenberg L (2011) Regular aspirin use and breast cancer risk in US Black women. Cancer Causes Control 22(11):1553–1561. doi: 10.1007/s10552-011-9832-6 PubMedGoogle Scholar
  224. 224.
    Garcia Rodriguez LA, Gonzalez-Perez A (2004) Risk of breast cancer among users of aspirin and other anti-inflammatory drugs. Br J Cancer 91(3):525–529. doi:10.1038/sj.bjc.6602003 6602003 [pii]PubMedGoogle Scholar
  225. 225.
    Rahme E, Ghosn J, Dasgupta K, Rajan R, Hudson M (2005) Association between frequent use of nonsteroidal anti-inflammatory drugs and breast cancer. BMC Cancer 5:159. doi:1471-­2407-5-159 [pii] 10.1186/1471-2407-5-159PubMedGoogle Scholar
  226. 226.
    Vinogradova Y, Coupland C, Hippisley-Cox J (2011) Exposure to cyclooxygenase-2 inhibitors and risk of cancer: nested case–control studies. Br J Cancer 105(3):452–459. doi:bjc2011252 [pii] 10.1038/bjc.2011.252PubMedGoogle Scholar
  227. 227.
    Valsecchi ME, Pomerantz SC, Jaslow R, Tester W (2009) Reduced risk of bone metastasis for patients with breast cancer who use COX-2 inhibitors. Clin Breast Cancer 9(4):225–230. doi:S1526-8209(11)70672-3 [pii] 10.3816/CBC.2009.n.038PubMedGoogle Scholar
  228. 228.
    Brasky TM, Bonner MR, Moysich KB, Ambrosone CB, Nie J, Tao MH, Edge SB, Kallakury BV, Marian C, Goerlitz DS, Trevisan M, Shields PG, Freudenheim JL (2011) Non-steroidal anti-inflammatory drugs (NSAIDs) and breast cancer risk: differences by molecular subtype. Cancer Causes Control 22(7):965–975. doi: 10.1007/s10552-011-9769-9 PubMedGoogle Scholar
  229. 229.
    Friis S, Thomassen L, Sorensen HT, Tjonneland A, Overvad K, Cronin-Fenton DP, Vogel U, McLaughlin JK, Blot WJ, Olsen JH (2008) Nonsteroidal anti-inflammatory drug use and breast cancer risk: a Danish cohort study. Eur J Cancer Prev 17(2):88–96. doi:10.1097/CEJ.0b013e3282b6fd55 00008469-200804000-00004 [pii]PubMedGoogle Scholar
  230. 230.
    Ready A, Velicer CM, McTiernan A, White E (2008) NSAID use and breast cancer risk in the VITAL cohort. Breast Cancer Res Treat 109(3):533–543. doi: 10.1007/s10549-007-9665-x PubMedGoogle Scholar
  231. 231.
    Cronin-Fenton DP, Pedersen L, Lash TL, Friis S, Baron JA, Sorensen HT (2010) Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case–control study. Breast Cancer Res 12(2):R15. doi:bcr2482 [pii] 10.1186/bcr2482PubMedGoogle Scholar
  232. 232.
    Egan KM, Stampfer MJ, Giovannucci E, Rosner BA, Colditz GA (1996) Prospective study of regular aspirin use and the risk of breast cancer. J Natl Cancer Inst 88(14):988–993PubMedGoogle Scholar
  233. 233.
    Eliassen AH, Chen WY, Spiegelman D, Willett WC, Hunter DJ, Hankinson SE (2009) Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and risk of breast cancer among premenopausal women in the Nurses' Health Study II. Arch Intern Med 169(2):115–121; discussion 121. doi:169/2/115 [pii] 10.1001/archinternmed.2008.537Google Scholar
  234. 234.
    Zhang X, Smith-Warner SA, Collins LC, Rosner B, Willett WC, Hankinson SE (2012) Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and postmenopausal breast cancer incidence. J Clin Oncol 30(28):3468–3477. doi:JCO.2012.42.2006 [pii] 10.1200/JCO.2012.42.2006PubMedGoogle Scholar
  235. 235.
    Jacobs EJ, Thun MJ, Connell CJ, Rodriguez C, Henley SJ, Feigelson HS, Patel AV, Flanders WD, Calle EE (2005) Aspirin and other nonsteroidal anti-inflammatory drugs and breast cancer incidence in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev 14(1):261–264PubMedGoogle Scholar
  236. 236.
    Gierach GL, Lacey JV Jr, Schatzkin A, Leitzmann MF, Richesson D, Hollenbeck AR, Brinton LA (2008) Nonsteroidal anti-inflammatory drugs and breast cancer risk in the National Institutes of Health-AARP Diet and Health Study. Breast Cancer Res 10(2):R38PubMedGoogle Scholar
  237. 237.
    Marshall SF, Bernstein L, Anton-Culver H, Deapen D, Horn-Ross PL, Mohrenweiser H, Peel D, Pinder R, Purdie DM, Reynolds P, Stram D, West D, Wright WE, Ziogas A, Ross RK (2005) Nonsteroidal anti-inflammatory drug use and breast cancer risk by stage and hormone receptor status. J Natl Cancer Inst 97(11):805–812PubMedGoogle Scholar
  238. 238.
    Gill JK, Maskarinec G, Wilkens LR, Pike MC, Henderson BE, Kolonel LN (2007) Nonsteroidal antiinflammatory drugs and breast cancer risk: the multiethnic cohort. Am J Epidemiol 166(10):1150–1158. doi:kwm195 [pii] 10.1093/aje/kwm195PubMedGoogle Scholar
  239. 239.
    Zhang Y, Coogan PF, Palmer JR, Strom BL, Rosenberg L (2005) Use of nonsteroidal antiinflammatory drugs and risk of breast cancer: the Case–Control Surveillance Study revisited. Am J Epidemiol 162(2):165–170. doi:kwi182 [pii] 10.1093/aje/kwi182PubMedGoogle Scholar
  240. 240.
    Gallicchio L, Visvanathan K, Burke A, Hoffman SC, Helzlsouer KJ (2007) Nonsteroidal anti-­inflammatory drugs and the risk of developing breast cancer in a population-based prospective cohort study in Washington County, MD. Int J Cancer 121(1):211–215. doi: 10.1002/ijc.22656 PubMedGoogle Scholar
  241. 241.
    Kirsh VA, Kreiger N, Cotterchio M, Sloan M, Theis B (2007) Nonsteroidal antiinflammatory drug use and breast cancer risk: subgroup findings. Am J Epidemiol 166(6):709–716. doi:kwm216 [pii] 10.1093/aje/kwm216PubMedGoogle Scholar
  242. 242.
    Bardia A, Olson JE, Vachon CM, Lazovich D, Vierkant RA, Wang AH, Limburg PJ, Anderson KE, Cerhan JR (2011) Effect of aspirin and other NSAIDs on postmenopausal breast cancer incidence by hormone receptor status: results from a prospective cohort study. Breast Cancer Res Treat 126(1):149–155. doi: 10.1007/s10549-010-1074-x PubMedGoogle Scholar
  243. 243.
    Blair CK, Sweeney C, Anderson KE, Folsom AR (2007) NSAID use and survival after breast cancer diagnosis in post-menopausal women. Breast Cancer Res Treat 101(2):191–197. doi: 10.1007/s10549-006-9277-x PubMedGoogle Scholar
  244. 244.
    Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE (2010) Aspirin intake and survival after breast cancer. J Clin Oncol 28(9):1467–1472. doi:JCO.2009.22.7918 [pii] 10.1200/JCO.2009.22.7918PubMedGoogle Scholar
  245. 245.
    Kwan ML, Habel LA, Slattery ML, Caan B (2007) NSAIDs and breast cancer recurrence in a prospective cohort study. Cancer Causes Control 18(6):613–620. doi: 10.1007/s10552-007-9003-y PubMedGoogle Scholar
  246. 246.
    Li Y, Brasky TM, Nie J, Ambrosone CB, McCann SE, Shields PG, Trevisan M, Edge SB, Freudenheim JL (2012) Use of nonsteroidal anti-inflammatory drugs and survival following breast cancer diagnosis. Cancer Epidemiol Biomarkers Prev 21(1):239–242. doi:1055–9965.EPI-11-1012 [pii] 10.1158/1055-9965.EPI-11-1012PubMedGoogle Scholar
  247. 247.
    Wernli KJ, Hampton JM, Trentham-Dietz A, Newcomb PA (2011) Use of antidepressants and NSAIDs in relation to mortality in long-term breast cancer survivors. Pharmacoepidemiol Drug Saf 20(2):131–137. doi: 10.1002/pds.2064 PubMedGoogle Scholar
  248. 248.
    Canney PA, Machin MA, Curto J (2006) A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor Celecoxib in post-menopausal patients with advanced breast cancer. Eur J Cancer 42(16):2751–2756. doi:S0959-­8049(06)00723-4 [pii] 10.1016/j.ejca.2006.08.014PubMedGoogle Scholar
  249. 249.
    Dang CT, Dannenberg AJ, Subbaramaiah K, Dickler MN, Moasser MM, Seidman AD, D’Andrea GM, Theodoulou M, Panageas KS, Norton L, Hudis CA (2004) Phase II study of celecoxib and trastuzumab in metastatic breast cancer patients who have progressed after prior trastuzumab-based treatments. Clin Cancer Res 10(12 pt 1):4062–4067. doi:10.1158/1078-0432.CCR-03-0463 10/12/4062 [pii]PubMedGoogle Scholar
  250. 250.
    Dirix LY, Ignacio J, Nag S, Bapsy P, Gomez H, Raghunadharao D, Paridaens R, Jones S, Falcon S, Carpentieri M, Abbattista A, Lobelle JP (2008) Treatment of advanced hormone-­sensitive breast cancer in postmenopausal women with exemestane alone or in combination with celecoxib. J Clin Oncol 26(8):1253–1259. doi:26/8/1253 [pii] 10.1200/JCO.2007.13.3744PubMedGoogle Scholar
  251. 251.
    Fabi A, Metro G, Papaldo P, Mottolese M, Melucci E, Carlini P, Sperduti I, Russillo M, Gelibter A, Ferretti G, Tomao S, Milella M, Cognetti F (2008) Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation. Cancer Chemother Pharmacol 62(4):717–725. doi: 10.1007/s00280-007-0650-1 PubMedGoogle Scholar
  252. 252.
    Chow LW, Yip AY, Loo WT, Lam CK, Toi M (2008) Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer. J Steroid Biochem Mol Biol 111(1–2):13–17. doi:S0960-0760(08)00089-7 [pii] 10.1016/j.jsbmb.2008.04.004PubMedGoogle Scholar
  253. 253.
    Sauter ER, Qin W, Schlatter L, Hewett JE, Flynn JT (2006) Celecoxib decreases prostaglandin E2 concentrations in nipple aspirate fluid from high risk postmenopausal women and women with breast cancer. BMC Cancer 6:248. doi:1471-2407-6-248 [pii] 10.1186/1471-2407-6-248PubMedGoogle Scholar
  254. 254.
    Bundred NJ, Cramer A, Morris J, Renshaw L, Cheung KL, Flint P, Johnson R, Young O, Landberg G, Grassby S, Turner L, Baildam A, Barr L, Dixon JM (2010) Cyclooxygenase-2 inhibition does not improve the reduction in ductal carcinoma in situ proliferation with aromatase inhibitor therapy: results of the ERISAC randomized placebo-controlled trial. Clin Cancer Res 16(5):1605–1612. doi:1078–0432.CCR-09-1623 [pii] 10.1158/1078-0432.CCR-09-1623PubMedGoogle Scholar
  255. 255.
    Martin LA, Davies GL, Weigel MT, Betambeau N, Hills MJ, Salter J, Walsh G, A’Hern R, Dowsett M (2010) Pre-surgical study of the biological effects of the selective cyclo-­oxygenase-2 inhibitor celecoxib in patients with primary breast cancer. Breast Cancer Res Treat 123(3):829–836. doi: 10.1007/s10549-010-1100-z PubMedGoogle Scholar
  256. 256.
    Lustberg MB, Povoski SP, Zhao W, Ziegler RM, Sugimoto Y, Ruppert AS, Lehman AM, Shiels DR, Mrozek E, Ramaswamy B, Layman RM, Brueggemeier RW, Shapiro CL (2011) Phase II trial of neoadjuvant exemestane in combination with celecoxib in postmenopausal women who have breast cancer. Clin Breast Cancer 11(4):221–227. doi:S1526-­8209(11)00035-8 [pii] 10.1016/j.clbc.2011.03.022PubMedGoogle Scholar
  257. 257.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545. doi:S0140-6736(00)04046-0 [pii] 10.1016/S0140-6736(00)04046-0PubMedGoogle Scholar
  258. 258.
    Harvey AE, Lashinger LM, Hursting SD (2011) The growing challenge of obesity and cancer: an inflammatory issue. Ann N Y Acad Sci 1229:45–52. doi: 10.1111/j.1749-6632.2011.06096.x PubMedGoogle Scholar
  259. 259.
    Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8(12):915–928. doi:nrc2536 [pii] 10.1038/nrc2536PubMedGoogle Scholar
  260. 260.
    Wong KK, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20(1):87–90. doi:S0959-437X(09)00178-6 [pii] 10.1016/j.gde.2009.11.002PubMedGoogle Scholar
  261. 261.
    Desbois-Mouthon C, Cadoret A, Blivet-Van Eggelpoel MJ, Bertrand F, Cherqui G, Perret C, Capeau J (2001) Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene 20(2):252–259. doi: 10.1038/sj.onc.1204064 PubMedGoogle Scholar
  262. 262.
    Giles RH, van Es JH, Clevers H (2003) Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653(1):1–24PubMedGoogle Scholar
  263. 263.
    Cleary MP, Grossmann ME, Ray A (2010) Effect of obesity on breast cancer development. Vet Pathol 47(2):202–213. doi:0300985809357753 [pii] 10.1177/0300985809357753PubMedGoogle Scholar
  264. 264.
    Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11(2):191–198. doi:nm1185 [pii] 10.1038/nm1185PubMedGoogle Scholar
  265. 265.
    Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11(2):183–190. doi:nm1166 [pii] 10.1038/nm1166PubMedGoogle Scholar
  266. 266.
    Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D, Delproposto JB, Blackwell TS, Yull FE, Saltiel AR (2009) The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138(5):961–975. doi:S0092-­8674(09)00793-4 [pii] 10.1016/j.cell.2009.06.046PubMedGoogle Scholar
  267. 267.
    Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293(5535):1673–1677. doi:10.1126/science.1061620 293/5535/1673 [pii]PubMedGoogle Scholar
  268. 268.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293. doi:S0092-8674(12)00351-0 [pii] 10.1016/j.cell.2012.03.017PubMedGoogle Scholar
  269. 269.
    Piazza GA, Alberts DS, Hixson LJ, Paranka NS, Li H, Finn T, Bogert C, Guillen JM, Brendel K, Gross PH, Sperl G, Ritchie J, Burt RW, Ellsworth L, Ahnen DJ, Pamukcu R (1997) Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res 57(14):2909–2915PubMedGoogle Scholar
  270. 270.
    Elder DJ, Halton DE, Hague A, Paraskeva C (1997) Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti- inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res 3(10):1679–1683PubMedGoogle Scholar
  271. 271.
    Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B (1996) Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 52(2):237–245PubMedGoogle Scholar
  272. 272.
    Zhang X, Morham SG, Langenbach R, Young DA (1999) Malignant transformation and antineoplastic actions of nonsteroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-null embryo fibroblasts. J Exp Med 190(4):451–459PubMedGoogle Scholar
  273. 273.
    Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN (1998) Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58(2):362–366PubMedGoogle Scholar
  274. 274.
    Chan TA, Morin PJ, Vogelstein B, Kinzler KW (1998) Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci U S A 95(2):681–686PubMedGoogle Scholar
  275. 275.
    Cao Y, Pearman AT, Zimmerman GA, McIntyre TM, Prescott SM (2000) Intracellular unesterified arachidonic acid signals apoptosis. Proc Natl Acad Sci U S A 97(21):11280–11285PubMedGoogle Scholar
  276. 276.
    Gupta RA, Tan J, Krause WF, Geraci MW, Willson TM, Dey SK, DuBois RN (2000) Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci U S A 97(24):13275–13280. doi:10.1073/pnas.97.24.13275 97/24/13275 [pii]PubMedGoogle Scholar
  277. 277.
    Cutler NS, Graves-Deal R, LaFleur BJ, Gao Z, Boman BM, Whitehead RH, Terry E, Morrow JD, Coffey RJ (2003) Stromal production of prostacyclin confers an antiapoptotic effect to colonic epithelial cells. Cancer Res 63(8):1748–1751PubMedGoogle Scholar
  278. 278.
    Piazza GA, Rahm AL, Krutzsch M, Sperl G, Paranka NS, Gross PH, Brendel K, Burt RW, Alberts DS, Pamukcu R, Ahnen DJ (1995) Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 55(14):3110–3116PubMedGoogle Scholar
  279. 279.
    Shureiqi I, Chen D, Lee JJ, Yang P, Newman RA, Brenner DE, Lotan R, Fischer SM, Lippman SM (2000) 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-­induced apoptosis in colorectal cancer cells. J Natl Cancer Inst 92(14):1136–1142PubMedGoogle Scholar
  280. 280.
    Wu J, Xia HH, Tu SP, Fan DM, Lin MC, Kung HF, Lam SK, Wong BC (2003) 15-Lipoxygenase-1 mediates cyclooxygenase-2 inhibitor-induced apoptosis in gastric cancer. Carcinogenesis 24(2):243–247PubMedGoogle Scholar
  281. 281.
    Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE (2001) Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol 59(4):901–908PubMedGoogle Scholar
  282. 282.
    Zhang Z, DuBois RN (2000) Par-4, a proapoptotic gene, is regulated by NSAIDs in human colon carcinoma cells. Gastroenterology 118(6):1012–1017. doi:S0016508500948704 [pii]PubMedGoogle Scholar
  283. 283.
    He TC, Chan TA, Vogelstein B, Kinzler KW (1999) PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99(3):335–345. doi:S0092-8674(00)81664-5 [pii]PubMedGoogle Scholar
  284. 284.
    Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, Ogier-Denis E (2002) Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem 277(31):27613–27621. doi:10.1074/jbc.M201119200 M201119200 [pii]PubMedGoogle Scholar
  285. 285.
    Liou JY, Ghelani D, Yeh S, Wu KK (2007) Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon. Cancer Res 67(7):3185–3191. doi:67/7/3185 [pii] 10.1158/0008-5472.CAN-06-3431PubMedGoogle Scholar
  286. 286.
    Ouyang N, Williams JL, Rigas B (2006) NO-donating aspirin isomers downregulate peroxisome proliferator-activated receptor (PPAR)delta expression in APC(min/+) mice proportionally to their tumor inhibitory effect: implications for the role of PPARdelta in carcinogenesis. Carcinogenesis 27(2):232–239. doi:bgi221 [pii] 10.1093/carcin/bgi221PubMedGoogle Scholar
  287. 287.
    Shureiqi I, Jiang W, Zuo X, Wu Y, Stimmel JB, Leesnitzer LM, Morris JS, Fan HZ, Fischer SM, Lippman SM (2003) The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells. Proc Natl Acad Sci U S A 100(17):9968–9973. doi:10.1073/pnas.1631086100 1631086100 [pii]PubMedGoogle Scholar
  288. 288.
    Qiu W, Wang X, Leibowitz B, Liu H, Barker N, Okada H, Oue N, Yasui W, Clevers H, Schoen RE, Yu J, Zhang L (2010) Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc Natl Acad Sci U S A 107(46):20027–20032. doi:1010430107 [pii] 10.1073/pnas.1010430107PubMedGoogle Scholar
  289. 289.
    Liou JY, Ellent DP, Lee S, Goldsby J, Ko BS, Matijevic N, Huang JC, Wu KK (2007) Cyclooxygenase-2-derived prostaglandin e2 protects mouse embryonic stem cells from apoptosis. Stem Cells 25(5):1096–1103. doi:2006–0505 [pii] 10.1634/stemcells.2006-0505PubMedGoogle Scholar
  290. 290.
    Boon EM, Keller JJ, Wormhoudt TA, Giardiello FM, Offerhaus GJ, van der Neut R, Pals ST (2004) Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br J Cancer 90(1):224–229. doi:10.1038/sj.bjc.6601505 6601505 [pii]PubMedGoogle Scholar
  291. 291.
    Bos CL, Kodach LL, van den Brink GR, Diks SH, van Santen MM, Richel DJ, Peppelenbosch MP, Hardwick JC (2006) Effect of aspirin on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A. Oncogene 25(49):6447–6456. doi:1209658 [pii] 10.1038/sj.onc.1209658PubMedGoogle Scholar
  292. 292.
    Dihlmann S, Siermann A, von Knebel Doeberitz M (2001) The nonsteroidal anti-­inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling. Oncogene 20(5):645–653. doi: 10.1038/sj.onc.1204123 PubMedGoogle Scholar
  293. 293.
    Greenspan EJ, Madigan JP, Boardman LA, Rosenberg DW (2011) Ibuprofen inhibits activation of nuclear {beta}-catenin in human colon adenomas and induces the phosphorylation of GSK-3{beta}. Cancer Prev Res (Phila) 4(1):161–171. doi:4/1/161 [pii] 10.1158/1940-6207.CAPR-10-0021Google Scholar
  294. 294.
    Shao J, Jung C, Liu C, Sheng H (2005) Prostaglandin E2 stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer. J Biol Chem 280(28):26565–26572. doi:M413056200 [pii] 10.1074/jbc.M413056200PubMedGoogle Scholar
  295. 295.
    Thompson WJ, Piazza GA, Li H, Liu L, Fetter J, Zhu B, Sperl G, Ahnen D, Pamukcu R (2000) Exisulind induction of apoptosis involves guanosine 3′,5′-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res 60(13):3338–3342PubMedGoogle Scholar
  296. 296.
    Tinsley HN, Gary BD, Keeton AB, Zhang W, Abadi AH, Reynolds RC, Piazza GA (2009) Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G. Mol Cancer Ther 8(12):3331–3340. doi:1535–7163.MCT-09-0758 [pii] 10.1158/1535-7163.MCT-09-0758PubMedGoogle Scholar
  297. 297.
    Tinsley HN, Gary BD, Thaiparambil J, Li N, Lu W, Li Y, Maxuitenko YY, Keeton AB, Piazza GA (2010) Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev Res (Phila) 3(10):1303–1313. doi:1940–6207.CAPR-10-0030 [pii] 10.1158/1940-6207.CAPR-10-0030Google Scholar
  298. 298.
    Harris RM, Hawker RJ, Langman MJ, Singh S, Waring RH (1998) Inhibition of phenolsulphotransferase by salicylic acid: a possible mechanism by which aspirin may reduce carcinogenesis. Gut 42(2):272–275PubMedGoogle Scholar
  299. 299.
    Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265(5174):956–959PubMedGoogle Scholar
  300. 300.
    Grilli M, Pizzi M, Memo M, Spano P (1996) Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science 274(5291):1383–1385PubMedGoogle Scholar
  301. 301.
    Yamamoto Y, Yin MJ, Lin KM, Gaynor RB (1999) Sulindac inhibits activation of the NF-kappaB pathway. J Biol Chem 274(38):27307–27314PubMedGoogle Scholar
  302. 302.
    Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396(6706):77–80. doi: 10.1038/23948 PubMedGoogle Scholar
  303. 303.
    Din FV, Stark LA, Dunlop MG (2005) Aspirin-induced nuclear translocation of NFkappaB and apoptosis in colorectal cancer is independent of p53 status and DNA mismatch repair proficiency. Br J Cancer 92(6):1137–1143. doi:6602455 [pii] 10.1038/sj.bjc.6602455PubMedGoogle Scholar
  304. 304.
    Loveridge CJ, MacDonald AD, Thoms HC, Dunlop MG, Stark LA (2008) The proapoptotic effects of sulindac, sulindac sulfone and indomethacin are mediated by nucleolar translocation of the RelA(p65) subunit of NF-kappaB. Oncogene 27(18):2648–2655. doi:1210891 [pii] 10.1038/sj.onc.1210891PubMedGoogle Scholar
  305. 305.
    Hsieh PS, Jin JS, Chiang CF, Chan PC, Chen CH, Shih KC (2009) COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver. Obesity (Silver Spring) 17(6):1150–1157. doi:oby2008674 [pii] 10.1038/oby.2008.674Google Scholar
  306. 306.
    Gonzalez-Ortiz M, Martinez-Abundis E, Balcazar-Munoz BR, Robles-Cervantes JA (2001) Inhibition of cyclooxygenase-1 or -2 on insulin sensitivity in healthy subjects. Horm Metab Res 33(4):250–253PubMedGoogle Scholar
  307. 307.
    Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI (2002) Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 109(10):1321–1326. doi: 10.1172/JCI14955 PubMedGoogle Scholar
  308. 308.
    Fleischman A, Shoelson SE, Bernier R, Goldfine AB (2008) Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31(2):289–294. doi:dc07-1338 [pii] 10.2337/dc07-1338PubMedGoogle Scholar
  309. 309.
    Shoelson SE, Lee J, Yuan M (2003) Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord 27(suppl 3):S49–S52. doi:10.1038/sj.ijo.0802501 0802501 [pii]PubMedGoogle Scholar
  310. 310.
    Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J, Shoelson SE (2008) Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci 1(1):36–43. doi: 10.1111/j.1752-8062.2008.00026.x PubMedGoogle Scholar
  311. 311.
    Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336(6083):918–922. doi:science.1215327 [pii] 10.1126/science.1215327PubMedGoogle Scholar
  312. 312.
    Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG (2012) Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 142(7):1504–1515 e1503. doi:S0016-5085(12)00313-7 [pii] 10.1053/j.gastro.2012.02.05Google Scholar
  313. 313.
    Brunelli C, Amici C, Angelini M, Fracassi C, Belardo G, Santoro MG (2012) The non-­steroidal anti-inflammatory drug indomethacin activates the eIF2alpha kinase PKR, causing a translational block in human colorectal cancer cells. Biochem J 443(2):379–386. doi:BJ20111236 [pii] 10.1042/BJ20111236PubMedGoogle Scholar
  314. 314.
    Marimuthu S, Chivukula RS, Alfonso LF, Moridani M, Hagen FK, Bhat GJ (2011) Aspirin acetylates multiple cellular proteins in HCT-116 colon cancer cells: identification of novel targets. Int J Oncol 39(5):1273–1283. doi: 10.3892/ijo.2011.1113 PubMedGoogle Scholar
  315. 315.
    Claria J, Serhan CN (1995) Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci U S A 92(21):9475–9479PubMedGoogle Scholar
  316. 316.
    Ruschoff J, Wallinger S, Dietmaier W, Bocker T, Brockhoff G, Hofstadter F, Fishel R (1998) Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Proc Natl Acad Sci U S A 95(19):11301–11306PubMedGoogle Scholar
  317. 317.
    He H, Xia HH, Wang JD, Gu Q, Lin MC, Zou B, Lam SK, Chan AO, Yuen MF, Kung HF, Wong BC (2006) Inhibition of human telomerase reverse transcriptase by nonsteroidal ­antiinflammatory drugs in colon carcinoma. Cancer 106(6):1243–1249. doi: 10. 1002/cncr.21694 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cell and Developmental BiologyWeill Cornell Medical CollegeNew YorkUSA

Personalised recommendations