New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis

  • Honor J. Hugo
  • C. Saunders
  • R. G. Ramsay
  • E. W. Thompson


The medicinal use of aspirin stretches back to ancient times, before it was manufactured in its pure form in the late 19th century. Its accepted mechanistic target, cyclooxygenase (COX), was discovered in the 1970s and since this landmark discovery, the therapeutic application of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has increased dramatically. The most significant benefits of NSAIDs are in conditions involving chronic inflammation (CI). Given the recognized role of CI in cancer development, the use of long-term NSAID treatment in the prevention of cancer is an enticing possibility. COX-2 is a key driver of CI, and here we review COX-2 expression as a predictor of survival in various cancer types, including breast. Obesity and post-partum involution are natural inflammatory states that are associated with increased breast cancer risk. We outline the COX-2 mediated mechanisms contributing to the growth of cancers. We dissect the cellular mechanism of epithelial-mesenchymal transition (EMT) and how COX-2 may induce this to facilitate tumor progression. Finally we examine the potential regulation of COX-2 by c-Myb, and the possible interplay between c-Myb/COX-2 in proliferation, and hypoxia inducible factor-1 alpha (HIF1α)/COX-2 in invasive pathways in breast cancer.


COX-2 Chronic inflammation c-Myb Breast cancer EMT HIF1α 



We thank Dr Kara Britt (Peter MacCallum Cancer Centre, VIC) for critiquing the manuscript. EWT was supported in part by the EMPathy National Collaborative Research Program funded by the National Breast Cancer Foundation, Australia, and National Health and Medical Research Council (NHMRC) Project Grant 1027527, CS by the Raine Foundation at the University of Western Australia, and RGR by the NHMRC. This study benefited from support by the Victorian Government’s Operational Infrastructure Support Program to St. Vincent’s Institute and the Peter MacCallum Cancer Institute.

Compliance with Ethical Standards

The authors affirm full compliance with the ethical standards outlined in the JMGBN Instructions to Authors.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Hemler M, Lands WE. Purification of the cyclooxygenase that forms prostaglandins. Demonstration of two forms of iron in the holoenzyme. J Biol Chem. 1976;251(18):5575–9.PubMedGoogle Scholar
  2. 2.
    Hemler ME, Lands WE. Biosynthesis of prostaglandins. Lipids. 1977;12(7):591–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Kam PC, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role. Anaesthesia. 2000;55(5):442–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Simmons DL. Variants of cyclooxygenase-1 and their roles in medicine. Thromb Res. 2003;110(5–6):265–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Roos KL, Simmons DL. Cyclooxygenase variants: the role of alternative splicing. Biochem Biophys Res Commun. 2005;338(1):62–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Yu Y, Fan J, Chen XS, Wang D, Klein-Szanto AJ, Campbell RL, et al. Genetic model of selective COX2 inhibition reveals novel heterodimer signaling. Nat Med. 2006;12(6):699–704.PubMedCrossRefGoogle Scholar
  7. 7.
    Harris RE, Casto BC, Harris ZM. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol. 2014;5(4):677–92.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Fang Y, Chen X, Bajpai M, Verma A, Das KM, Souza RF, et al. Cellular origins and molecular mechanisms of Barrett’s esophagus and esophageal adenocarcinoma. Ann N Y Acad Sci. 2013;1300:187–99.PubMedCrossRefGoogle Scholar
  9. 9.
    Bornschein J, Wex T, Peitz U, Kuester D, Roessner A, Malfertheiner P. The combined presence of H pylori infection and gastro-oesophageal reflux disease leads to an up-regulation of CDX2 gene expression in antrum and cardia. J Clin Pathol. 2009;62(3):254–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Scarpa M, Castagliuolo I, Castoro C, Pozza A, Scarpa M, Kotsafti A, et al. Inflammatory colonic carcinogenesis: a review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis. World J Gastroenterol. 2014;20(22):6774–85.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    van Verschuer VM, Hooning MJ, van Baare-Georgieva RD, Hollestelle A, Timmermans AM, Koppert LB, et al. Tumor-associated inflammation as a potential prognostic tool in BRCA1/2-associated breast cancer. Hum Pathol. 2015;46(2):182–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013;138(2):105–15.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Beury DW, Parker KH, Nyandjo M, Sinha P, Carter KA, Ostrand-Rosenberg S. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol. 2014;96(6):1109–18.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Hugo HJ, Lebret S, Tomaskovic-Crook E, Ahmed N, Blick T, Newgreen DF, et al. Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment. Cancer Microenviron. 2012.Google Scholar
  16. 16.
    Danelli L, Frossi B, Gri G, Mion F, Guarnotta C, Bongiovanni L, et al. Mast cells boost myeloid-derived suppressor cell activity and contribute to the development of tumor-favoring microenvironment. Cancer Immunol Res. 2015;3(1):85–95.PubMedCrossRefGoogle Scholar
  17. 17.
    Pasche B, Wang M, Pennison M, Jimenez H. Prevention and treatment of cancer with aspirin: where do we stand? Semin Oncol. 2014;41(3):397–401.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Luo T, Yan HM, He P, Luo Y, Yang YF, Zheng H. Aspirin use and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2012;131(2):581–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Mangiapane S, Blettner M, Schlattmann P. Aspirin use and breast cancer risk: a meta-analysis and meta-regression of observational studies from 2001 to 2005. Pharmacoepidemiol Drug Saf. 2008;17(2):115–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhao YS, Zhu S, Li XW, Wang F, Hu FL, Li DD, et al. Association between NSAIDs use and breast cancer risk: a systematic review and meta-analysis. Breast Cancer Res Treat. 2009;117(1):141–50.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang X, Smith-Warner SA, Collins LC, Rosner B, Willett WC, Hankinson SE. Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and postmenopausal breast cancer incidence. J Clin Oncol. 2012;30(28):3468–77.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Brasky TM, Bonner MR, Moysich KB, Ochs-Balcom HM, Marian C, Ambrosone CB, et al. Genetic variants in COX-2, non-steroidal anti-inflammatory drugs, and breast cancer risk: the Western New York Exposures and Breast Cancer (WEB) Study. Breast Cancer Res Treat. 2011;126(1):157–65.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31(5):986–1000.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Ghosh AK. Regulation by prostaglandin E2 and histamine of angiogenesis in inflammatory granulation tissue. Yakugaku Zasshi. 2003;123(5):295–303.PubMedCrossRefGoogle Scholar
  25. 25.
    Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 2009;30(3):377–86.PubMedCrossRefGoogle Scholar
  26. 26.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Kroemer A, Edtinger K, Li XC. The innate natural killer cells in transplant rejection and tolerance induction. Curr Opin Organ Transplant. 2008;13(4):339–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Magnowska M, Zaborowski M, Surowiak P, Nowak-Markwitz E, Zabel M, Spaczynski M. COX-2 expression pattern is related to ovarian cancer differentiation and prognosis, but is not consistent with new model of pathogenesis. Ginekol Pol. 2014;85(5):335–41.PubMedGoogle Scholar
  29. 29.
    Lee TS, Lee JY, Kim JW, Oh S, Seong SJ, Lee JM, et al. Outcomes of ovarian preservation in a cohort of premenopausal women with early-stage endometrial cancer: a Korean Gynecologic Oncology Group study. Gynecol Oncol. 2013;131(2):289–93.PubMedCrossRefGoogle Scholar
  30. 30.
    Jiao G, Ren T, Lu Q, Sun Y, Lou Z, Peng X, et al. Prognostic significance of cyclooxygenase-2 in osteosarcoma: a meta-analysis. Tumour Biol. 2013;34(5):2489–95.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang Z, He M, Xiao Z, Wu H, Wu Y. Quantitative assessment of the association of COX-2 (Cyclooxygenase-2) immunoexpression with prognosis in human osteosarcoma: a meta-analysis. PLoS One. 2013;8(12), e82907.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Wang D, Guo XZ, Li HY, Zhao JJ, Shao XD, Wu CY. Prognostic significance of cyclooxygenase-2 protein in pancreatic cancer: a meta-analysis. Tumour Biol. 2014;35(10):10301–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Song J, Su H, Zhou YY, Guo LL. Cyclooxygenase-2 expression is associated with poor overall survival of patients with gastric cancer: a meta-analysis. Dig Dis Sci. 2014;59(2):436–45.PubMedCrossRefGoogle Scholar
  34. 34.
    Fanelli MF, Chinen LT, Begnami MD, Costa Jr WL, Fregnami JH, Soares FA, et al. The influence of transforming growth factor-alpha, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer. Histopathology. 2012;61(2):153–61.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang X, Wu Q, Gan L, Yu GZ, Wang R, Wang ZS, et al. Reduced group IVA phospholipase A2 expression is associated with unfavorable outcome for patients with gastric cancer. Med Oncol. 2013;30(1):454.PubMedCrossRefGoogle Scholar
  36. 36.
    Koh YW, Park C, Yoon DH, Suh C, Huh J. Prognostic significance of COX-2 expression and correlation with Bcl-2 and VEGF expression, microvessel density, and clinical variables in classical Hodgkin lymphoma. Am J Surg Pathol. 2013;37(8):1242–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Kono M, Watanabe M, Abukawa H, Hasegawa O, Satomi T, Chikazu D. Cyclo-oxygenase-2 expression is associated with vascular endothelial growth factor C expression and lymph node metastasis in oral squamous cell carcinoma. J Oral Maxillofac Surg. 2013;71(10):1694–702.PubMedCrossRefGoogle Scholar
  38. 38.
    Minisini AM, Pascoletti G, Intersimone D, Poletto E, Driol P, Spizzo R, et al. Expression of thymidine phosphorylase and cyclooxygenase-2 in melanoma. Melanoma Res. 2013;23(2):96–101.PubMedCrossRefGoogle Scholar
  39. 39.
    Jiang H, Wang J, Zhao W. Cox-2 in non-small cell lung cancer: a meta-analysis. Clin Chim Acta. 2013;419:26–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Turk HM, Camci C, Sevinc A, Bukyukberber S, Sari I, Adli M. Cyclooxygenase-2 expression is not a marker of poor survival in lung cancer. Asian Pac J Cancer Prev. 2012;13(1):315–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Lee JW, Park JH, Suh JH, Nam KH, Choe JY, Jung HY, et al. Cyclooxygenase-2 expression and its prognostic significance in clear cell renal cell carcinoma. Korean J Pathol. 2012;46(3):237–45.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Huang M, Chen Q, Xiao J, Liu C, Zhao X. Prognostic significance of cyclooxygenase-2 in cervical cancer: a meta-analysis. Int J Cancer. 2013;132(2):363–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Prins MJ, Verhage RJ, ten Kate FJ, van Hillegersberg R. Cyclooxygenase isoenzyme-2 and vascular endothelial growth factor are associated with poor prognosis in esophageal adenocarcinoma. J Gastrointest Surg. 2012;16(5):956–66.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Stocks J, Bradbury D, Corbett L, Pang L, Knox AJ. Cytokines upregulate vascular endothelial growth factor secretion by human airway smooth muscle cells: role of endogenous prostanoids. FEBS Lett. 2005;579(12):2551–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Prosperi JR, Mallery SR, Kigerl KA, Erfurt AA, Robertson FM. Invasive and angiogenic phenotype of MCF-7 human breast tumor cells expressing human cyclooxygenase-2. Prostaglandins Other Lipid Mediat. 2004;73(3–4):249–64.PubMedCrossRefGoogle Scholar
  46. 46.
    Angelo LS, Kurzrock R. Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res. 2007;13(10):2825–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Morita Y, Morita N, Hata K, Nakanishi M, Kimoto N, Omata T, et al. Cyclooxygenase-2 expression is associated with vascular endothelial growth factor-c and lymph node metastasis in human oral tongue cancer. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(4):502–10.PubMedCrossRefGoogle Scholar
  48. 48.
    Lin PC, Lin YJ, Lee CT, Liu HS, Lee JC. Cyclooxygenase-2 expression in the tumor environment is associated with poor prognosis in colorectal cancer patients. Oncol Lett. 2013;6(3):733–9.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Kunzmann AT, Murray LJ, Cardwell CR, McShane CM, McMenamin UC, Cantwell MM. PTGS2 (Cyclooxygenase-2) expression and survival among colorectal cancer patients: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22(9):1490–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Peng L, Zhou Y, Wang Y, Mou H, Zhao Q. Prognostic significance of COX-2 immunohistochemical expression in colorectal cancer: a meta-analysis of the literature. PLoS One. 2013;8(3), e58891.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Miladi-Abdennadher I, Abdelmaksoud-Dammak R, Ayed-Guerfali DB, Ayadi L, Khabir A, Amouri A, et al. Expression of COX-2 and E-cadherin in Tunisian patients with colorectal adenocarcinoma. Acta Histochem. 2012;114(6):577–81.PubMedCrossRefGoogle Scholar
  52. 52.
    Al-Maghrabi J, Buhmeida A, Emam E, Syrjanen K, Sibiany A, Al-Qahtani M, et al. Cyclooxygenase-2 expression as a predictor of outcome in colorectal carcinoma. World J Gastroenterol. 2012;18(15):1793–9.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Elzagheid A, Emaetig F, Alkikhia L, Buhmeida A, Syrjanen K, El-Faitori O, et al. High cyclooxygenase-2 expression is associated with advanced stages in colorectal cancer. Anticancer Res. 2013;33(8):3137–43.PubMedGoogle Scholar
  54. 54.
    Uhlmann ME, Georgieva M, Sill M, Linnemann U, Berger MR. Prognostic value of tumor progression-related gene expression in colorectal cancer patients. J Cancer Res Clin Oncol. 2012;138(10):1631–40.PubMedCrossRefGoogle Scholar
  55. 55.
    Choi CH, Lee TB, Lee YA, Choi S, Kim KJ. Up-regulation of cyclooxygenase-2-derived prostaglandin E(2) in colon cancer cells resistant to 5-fluorouracil. J Korean Surg Soc. 2011;81(2):115–21.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Kaur J, Sanyal SN. Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1alpha and VEGF. Mol Carcinog. 2011;50(9):707–18.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang L, Chen W, Xie X, He Y, Bai X. Celecoxib inhibits tumor growth and angiogenesis in an orthotopic implantation tumor model of human colon cancer. Exp Oncol. 2008;30(1):42–51.PubMedGoogle Scholar
  58. 58.
    Abdelrahim M, Safe S. Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharmacol. 2005;68(2):317–29.PubMedGoogle Scholar
  59. 59.
    Jana D, Sarkar DK, Ganguly S, Saha S, Sa G, Manna AK, et al. Role of cyclooxygenase 2 (COX-2) in prognosis of breast cancer. Indian J Surg Oncol. 2014;5(1):59–65.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Gawthorpe S, Brown JE, Arif M, Nightingale P, Nevill A, Carmichael AR. Heparanase and COX-2 expression as predictors of lymph node metastasis in large, high-grade breast tumors. Anticancer Res. 2014;34(6):2797–800.PubMedGoogle Scholar
  61. 61.
    Fornetti J, Jindal S, Middleton KA, Borges VF, Schedin P. Physiological COX-2 expression in breast epithelium associates with COX-2 levels in ductal carcinoma in situ and invasive breast cancer in young women. Am J Pathol. 2014;184(4):1219–29.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Sun L, Yu DH, Sun SY, Zhuo SC, Cao SS, Wei L. Expressions of ER, PR, HER-2, COX-2, and VEGF in primary and relapsed/metastatic breast cancers. Cell Biochem Biophys. 2014;68(3):511–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Jana D, Sarkar DK, Maji A, Chikkala BR, Hassanujjaman S, Mukhopadhyay M, et al. Can cyclo-oxygenase-2 be a useful prognostic and risk stratification marker in breast cancer? J Indian Med Assoc. 2012;110(7):429–33.PubMedGoogle Scholar
  64. 64.
    Kerlikowske K, Molinaro AM, Gauthier ML, Berman HK, Waldman F, Bennington J, et al. Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Natl Cancer Inst. 2010;102(9):627–37.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    de la Torre J, Sabadell MD, Rojo F, Lirola JL, Salicru S, Reventos J, et al. Cyclo-oxygenase type 2 is dysregulated in breast ductal carcinoma in situ and correlates with poor outcome. Eur J Obstet Gynecol Reprod Biol. 2010;151(1):72–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Holmes MD, Chen WY, Schnitt SJ, Collins L, Colditz GA, Hankinson SE, et al. COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin. Breast Cancer Res Treat. 2011;130(2):657–62.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Miglietta A, Toselli M, Ravarino N, Vencia W, Chiecchio A, Bozzo F, et al. COX-2 expression in human breast carcinomas: correlation with clinicopathological features and prognostic molecular markers. Expert Opin Ther Targets. 2010;14(7):655–64.PubMedCrossRefGoogle Scholar
  68. 68.
    Generali D, Buffa FM, Deb S, Cummings M, Reid LE, Taylor M, et al. COX-2 expression is predictive for early relapse and aromatase inhibitor resistance in patients with ductal carcinoma in situ of the breast, and is a target for treatment. Br J Cancer. 2014;111(1):46–54.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Park BW, Park S, Park HS, Koo JS, Yang WI, Lee JS, et al. Cyclooxygenase-2 expression in proliferative Ki-67-positive breast cancers is associated with poor outcomes. Breast Cancer Res Treat. 2012;133(2):741–51.PubMedCrossRefGoogle Scholar
  70. 70.
    Kargi A, Uysal M, Bozcuk H, Coskun HS, Savas B, Ozdogan M. The importance of COX-2 expression as prognostic factor in early breast cancer. J BUON. 2013;18(3):579–84.PubMedGoogle Scholar
  71. 71.
    Mosalpuria K, Hall C, Krishnamurthy S, Lodhi A, Hallman DM, Baraniuk MS, et al. Cyclooxygenase-2 expression in non-metastatic triple-negative breast cancer patients. Mol Clin Oncol. 2014;2(5):845–50.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Barisik NO, Keser SH, Gul AE, Sensu S, Kandemir NO, Kucuk HF, et al. The value of COX-2 expression in the prognostic parameters of invasive ductal carcinoma of the breast. Med Oncol. 2011;28(3):703–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Zhang H, Lin Y, Xiao Y, Wang SM, Liu XX, Wang SM. Stable transfection of estrogen receptor-alpha suppresses expression of cyclooxygenase-2 and vascular endothelial growth factor-C in MDA-MB-231 breast cancer cells. Chin Med J (Engl). 2010;123(15):1989–94.Google Scholar
  74. 74.
    Nassar A, Radhakrishnan A, Cabrero IA, Cotsonis G, Cohen C. COX-2 expression in invasive breast cancer: correlation with prognostic parameters and outcome. Appl Immunohistochem Mol Morphol. 2007;15(3):255–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Giri D, et al. Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov. 2012;2(4):356–65.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Glynn SA, Prueitt RL, Ridnour LA, Boersma BJ, Dorsey TM, Wink DA, et al. COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer. BMC Cancer. 2010;10:626.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Ives AD, Saunders CM, Semmens JB. The Western Australian gestational breast cancer project: a population-based study of the incidence, management and outcomes. Breast. 2005;14(4):276–82.PubMedCrossRefGoogle Scholar
  78. 78.
    Johansson AL, Andersson TM, Hsieh CC, Cnattingius S, Lambe M. Increased mortality in women with breast cancer detected during pregnancy and different periods postpartum. Cancer Epidemiol Biomarkers Prev. 2011;20(9):1865–72.PubMedCrossRefGoogle Scholar
  79. 79.
    Ives A, Saunders C, Bulsara M, Semmens J. Survival in young women diagnosed with breast cancer. Does pregnancy status make a difference? EJC Suppl. 2010;8(3):206.CrossRefGoogle Scholar
  80. 80.
    Schere-Levy C, Buggiano V, Quaglino A, Gattelli A, Cirio MC, Piazzon I, et al. Leukemia inhibitory factor induces apoptosis of the mammary epithelial cells and participates in mouse mammary gland involution. Exp Cell Res. 2003;282(1):35–47.PubMedCrossRefGoogle Scholar
  81. 81.
    Tiffen PG, Omidvar N, Marquez-Almuina N, Croston D, Watson CJ, Clarkson RW. A dual role for oncostatin M signaling in the differentiation and death of mammary epithelial cells in vivo. Mol Endocrinol. 2008;22(12):2677–88.PubMedCrossRefGoogle Scholar
  82. 82.
    Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res. 2004;6(2):R75–91.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Lyons TR, O’Brien J, Borges VF, Conklin MW, Keely PJ, Eliceiri KW, et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med. 2011;17(9):1109–15.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Ives A, Harvey J, Sterrett G, Semmens J, Saunders C. The pathological characteristics of gestational breast cancer. What is different? In San Antonio Breast Cancer Symposium 2007: San Antonio, USA.Google Scholar
  85. 85.
    Ives A, Saunders C, Harvey J, Semmens J. The histopathological profile of gestational breast cancer. In European Breast Cancer Conference 2006: Nice, France.Google Scholar
  86. 86.
    O’Brien J, Lyons T, Monks J, Lucia MS, Wilson RS, Hines L, et al. Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am J Pathol. 2010;176(3):1241–55.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Yang WT, Lewis MT, Hess K, Wong H, Tsimelzon A, Karadag N, et al. Decreased TGFbeta signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res Treat. 2010;119(2):305–14.PubMedCrossRefGoogle Scholar
  88. 88.
    Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83.PubMedCrossRefGoogle Scholar
  89. 89.
    Gunasinghe NP, Wells A, Thompson EW, Hugo HJ. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 2012;31(3–4):469–78.PubMedCrossRefGoogle Scholar
  90. 90.
    Blick T, Widodo E, Hugo H, Waltham M, Lenburg ME, Neve RM, et al. Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis. 2008;25(6):629–42.PubMedCrossRefGoogle Scholar
  91. 91.
    Tomlinson DC, Baxter EW, Loadman PM, Hull MA, Knowles MA. FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCgamma/COX-2-mediated mechanisms. PLoS One. 2012;7(6), e38972.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Ogunwobi OO, Liu C. Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways. Clin Exp Metastasis. 2011;28(8):721–31.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Rasanen K, Vaheri A. TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes. J Dermatol Sci. 2010;58(2):97–104.PubMedCrossRefGoogle Scholar
  94. 94.
    Jang TJ. Epithelial to mesenchymal transition in cutaneous squamous cell carcinoma is correlated with COX-2 expression but not with the presence of stromal macrophages or CD10-expressing cells. Virchows Arch. 2012;460(5):481–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Shimokawa M, Haraguchi M, Kobayashi W, Higashi Y, Matsushita S, Kawai K, et al. The transcription factor Snail expressed in cutaneous squamous cell carcinoma induces epithelial-mesenchymal transition and down-regulates COX-2. Biochem Biophys Res Commun. 2013;430(3):1078–82.PubMedCrossRefGoogle Scholar
  96. 96.
    Bocca C, Bozzo F, Miglietta A. COX2 inhibitor NS398 reduces HT-29 cell invasiveness by modulating signaling pathways mediated by EGFR and HIF1-alpha. Anticancer Res. 2014;34(4):1793–800.PubMedGoogle Scholar
  97. 97.
    Neil JR, Johnson KM, Nemenoff RA, Schiemann WP. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis. 2008;29(11):2227–35.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Mohammad MA, Zeeneldin AA, Abd Elmageed ZY, Khalil EH, Mahdy SM, Sharada HM, et al. Clinical relevance of cyclooxygenase-2 and matrix metalloproteinases (MMP-2 and MT1-MMP) in human breast cancer tissue. Mol Cell Biochem. 2012;366(1–2):269–75.PubMedCrossRefGoogle Scholar
  99. 99.
    Pulyaeva H, Bueno J, Polette M, Birembaut P, Sato H, Seiki M, et al. MT1-MMP correlates with MMP-2 activation potential seen after epithelial to mesenchymal transition in human breast carcinoma cells. Clin Exp Metastasis. 1997;15(2):111–20.PubMedCrossRefGoogle Scholar
  100. 100.
    Gong L, Thorn CF, Bertagnolli MM, Grosser T, Altman RB, Klein TE. Celecoxib pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22(4):310–8.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Fujii R, Imanishi Y, Shibata K, Sakai N, Sakamoto K, Shigetomi S, et al. Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma. J Exp Clin Cancer Res. 2014;33:40.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Bozzo F, Bassignana A, Lazzarato L, Boschi D, Gasco A, Bocca C, et al. Novel nitro-oxy derivatives of celecoxib for the regulation of colon cancer cell growth. Chem Biol Interact. 2009;182(2–3):183–90.PubMedCrossRefGoogle Scholar
  103. 103.
    Jang TJ, Cha WH, Lee KS. Reciprocal correlation between the expression of cyclooxygenase-2 and E-cadherin in human bladder transitional cell carcinomas. Virchows Arch. 2010;457(3):319–28.PubMedCrossRefGoogle Scholar
  104. 104.
    Bocca C, Ievolella M, Autelli R, Motta M, Mosso L, Torchio B, et al. Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness. Expert Opin Ther Targets. 2014;18(2):121–35.PubMedCrossRefGoogle Scholar
  105. 105.
    Adhim Z, Matsuoka T, Bito T, Shigemura K, Lee KM, Kawabata M, et al. In vitro and in vivo inhibitory effect of three Cox-2 inhibitors and epithelial-to-mesenchymal transition in human bladder cancer cell lines. Br J Cancer. 2011;105(3):393–402.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Kirane A, Toombs JE, Ostapoff K, Carbon JG, Zaknoen S, Braunfeld J, et al. Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer. Clin Cancer Res. 2012;18(18):5031–42.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    St John MA, Wang G, Luo J, Dohadwala M, Hu D, Lin Y, et al. Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies. Br J Cancer. 2012;107(4):707–12.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Dohadwala M, Yang SC, Luo J, Sharma S, Batra RK, Huang M, et al. Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res. 2006;66(10):5338–45.PubMedCrossRefGoogle Scholar
  109. 109.
    Wang ZL, Fan ZQ, Jiang HD, Qu JM. Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling. Carcinogenesis. 2013;34(3):638–46.PubMedCrossRefGoogle Scholar
  110. 110.
    Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820–5.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 2012;21(1):66–81.PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Ramsay RG, Gonda TJ. MYB function in normal and cancer cells. Nat Rev Cancer. 2008;8(7):523–34.PubMedCrossRefGoogle Scholar
  113. 113.
    Ernst M, Ramsay RG. Colorectal cancer mouse models: integrating inflammation and the stroma. J Gastroenterol Hepatol. 2012;27(1):39–50.PubMedCrossRefGoogle Scholar
  114. 114.
    Ramsay RG, Friend A, Vizantios Y, Freeman R, Sicurella C, Hammett F, et al. Cyclooxygenase-2, a colorectal cancer nonsteroidal anti-inflammatory drug target, is regulated by c-MYB. Cancer Res. 2000;60(7):1805–9.PubMedGoogle Scholar
  115. 115.
    Bhattarai G, Lee YH, Lee NH, Yun JS, Hwang PH, Yi HK. c-myb mediates inflammatory reaction against oxidative stress in human breast cancer cell line, MCF-7. Cell Biochem Funct. 2011;29(8):686–93.PubMedCrossRefGoogle Scholar
  116. 116.
    Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007;67(8):3496–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Juin P, Geneste O, Gautier F, Depil S, Campone M. Decoding and unlocking the BCL-2 dependency of cancer cells. Nat Rev Cancer. 2013;13(7):455–65.PubMedCrossRefGoogle Scholar
  118. 118.
    Ramsay RG, Ciznadija D, Mantamadiotis T, Anderson R, Pearson R. Expression of stress response protein glucose regulated protein-78 mediated by c-Myb. Int J Biochem Cell Biol. 2005;37(6):1254–68.PubMedCrossRefGoogle Scholar
  119. 119.
    Thompson MA, Rosenthal MA, Ellis SL, Friend AJ, Zorbas MI, Whitehead RH, et al. c-Myb down-regulation is associated with human colon cell differentiation, apoptosis, and decreased Bcl-2 expression. Cancer Res. 1998;58(22):5168–75.PubMedGoogle Scholar
  120. 120.
    Miao RY, Drabsch Y, Cross RS, Cheasley D, Carpinteri S, Pereira L, et al. MYB is essential for mammary tumorigenesis. Cancer Res. 2011;71(22):7029–37.PubMedCrossRefGoogle Scholar
  121. 121.
    Drabsch Y, Hugo H, Zhang R, Dowhan DH, Miao YR, Gewirtz AM, et al. Mechanism of and requirement for estrogen-regulated MYB expression in estrogen-receptor-positive breast cancer cells. Proc Natl Acad Sci U S A. 2007;104(34):13762–7.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Mitra P, Pereira LA, Drabsch Y, Ramsay RG, Gonda TJ. Estrogen receptor-alpha recruits P-TEFb to overcome transcriptional pausing in intron 1 of the MYB gene. Nucleic Acids Res. 2012;40(13):5988–6000.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Vantaggiato C, Tocchetti M, Cappelletti V, Gurtner A, Villa A, Daidone MG, et al. Cell cycle dependent oscillatory expression of estrogen receptor-alpha links Pol II elongation to neoplastic transformation. Proc Natl Acad Sci U S A. 2014;111(26):9561–6.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Kauraniemi P, Hedenfalk I, Persson K, Duggan DJ, Tanner M, Johannsson O, et al. MYB oncogene amplification in hereditary BRCA1 breast cancer. Cancer Res. 2000;60(19):5323–8.PubMedGoogle Scholar
  125. 125.
    Guerin M, Sheng ZM, Andrieu N, Riou G. Strong association between c-myb and oestrogen-receptor expression in human breast cancer. Oncogene. 1990;5(1):131–5.PubMedGoogle Scholar
  126. 126.
    Hugo HJ, Pereira L, Suryadinata R, Drabsch Y, Gonda TJ, Gunasinghe NP, et al. Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression during epithelial-to-mesenchymal transition of breast cancer cells. Breast Cancer Res. 2013;15(6):R113.PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Wells A, Griffith L, Wells JZ, Taylor DP. The dormancy dilemma: quiescence versus balanced proliferation. Cancer Res. 2013;73(13):3811–6.PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Zhang XH, Giuliano M, Trivedi MV, Schiff R, Osborne CK. Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res. 2013;19(23):6389–97.PubMedCrossRefGoogle Scholar
  129. 129.
    Thompson MA, Ramsay RG. Myb: an old oncoprotein with new roles. Bioessays. 1995;17(4):341–50.PubMedCrossRefGoogle Scholar
  130. 130.
    Ramsay RG, Ishii S, Gonda TJ. Interaction of the Myb protein with specific DNA binding sites. J Biol Chem. 1992;267(8):5656–62.PubMedGoogle Scholar
  131. 131.
    Campanero MR, Armstrong M, Flemington E. Distinct cellular factors regulate the c-myb promoter through its E2F element. Mol Cell Biol. 1999;19(12):8442–50.PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Davis JN, McCabe MT, Hayward SW, Park JM, Day ML. Disruption of Rb/E2F pathway results in increased cyclooxygenase-2 expression and activity in prostate epithelial cells. Cancer Res. 2005;65(9):3633–42.PubMedCrossRefGoogle Scholar
  133. 133.
    Witkiewicz AK, Cox DW, Rivadeneira D, Ertel AE, Fortina P, Schwartz GF, et al. The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer. Oncogene. 2014;33(30):3980–91.PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Kopecki Z, Luchetti MM, Adams DH, Strudwick X, Mantamadiotis T, Stoppacciaro A, et al. Collagen loss and impaired wound healing is associated with c-Myb deficiency. J Pathol. 2007;211(3):351–61.PubMedCrossRefGoogle Scholar
  135. 135.
    Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science. 2005;310(5753):1504–10.PubMedCrossRefGoogle Scholar
  136. 136.
    Ciznadija D, Tothill R, Waterman ML, Zhao L, Huynh D, Yu RM, et al. Intestinal adenoma formation and MYC activation are regulated by cooperation between MYB and Wnt signaling. Cell Death Differ. 2009;16(11):1530–8.PubMedCrossRefGoogle Scholar
  137. 137.
    Germann M, Xu H, Malaterre J, Sampurno S, Huyghe M, Cheasley D, et al. Tripartite interactions between Wnt signaling, Notch and Myb for stem/progenitor cell functions during intestinal tumorigenesis. Stem Cell Res. 2014;13(3 Pt A):355–66.PubMedCrossRefGoogle Scholar
  138. 138.
    Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, et al. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma. BMC Cancer. 2013;13:108.PubMedCentralPubMedCrossRefGoogle Scholar
  139. 139.
    Zhu GH, Huang C, Feng ZZ, Lv XH, Qiu ZJ. Hypoxia-induced snail expression through transcriptional regulation by HIF-1alpha in pancreatic cancer cells. Dig Dis Sci. 2013;58(12):3503–15.PubMedCrossRefGoogle Scholar
  140. 140.
    Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, et al. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem. 2002;277(42):39209–16.PubMedCrossRefGoogle Scholar
  141. 141.
    Hugo HJ, Kokkinos MI, Blick T, Ackland ML, Thompson EW, Newgreen DF. Defining the E-cadherin repressor interactome in epithelial-mesenchymal transition: the PMC42 model as a case study. Cells Tissues Organs. 2011;193(1–2):23–40.PubMedCrossRefGoogle Scholar
  142. 142.
    Ryu K, Park C, Lee Y. Hypoxia-inducible factor 1 alpha represses the transcription of the estrogen receptor alpha gene in human breast cancer cells. Biochem Biophys Res Commun. 2011;407(4):831–6.PubMedCrossRefGoogle Scholar
  143. 143.
    Kaidi A, Williams AC, Paraskeva C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol. 2007;9(2):210–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Kaidi A, Qualtrough D, Williams AC, Paraskeva C. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 2006;66(13):6683–91.PubMedCrossRefGoogle Scholar
  145. 145.
    Sampurno S, Cross RS, Pearson R, Kaur P, Malaterre J, Ramsay RG. Myb via TGF-beta is required for Collagen Type 1 Production and Skin Integrity. Growth Factors (in press) 2015.Google Scholar
  146. 146.
    Lin SJ, Cawson J, Hill P, Haviv I, Jenkins M, Hopper JL, et al. Image-guided sampling reveals increased stroma and lower glandular complexity in mammographically dense breast tissue. Breast Cancer Res Treat. 2011;128(2):505–16.PubMedCrossRefGoogle Scholar
  147. 147.
    Huo CW, Chew G, Hill P, Huang D, Ingman W, Hodson L, et al. High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium. Breast Cancer Res. 2015;17(1):79.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.VBCRC Invasion and Metastasis UnitSt Vincent’s InstituteFitzroyAustralia
  2. 2.School of SurgeryUniversity of Western AustraliaPerthAustralia
  3. 3.Differentation and Transcription Laboratory, Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneAustralia
  4. 4.Institute of Health and Biomedical Innovation and School of Biomedical SciencesQueensland Institute of TechnologyBrisbaneAustralia
  5. 5.Department of Surgery, St Vincent’s HospitalUniversity of MelbourneMelbourneAustralia

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