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

Journal of Mammary Gland Biology and Neoplasia

Volumn 20, Issue 3-4, 2015, Pages 109-119

  Hugo, Honor J ^a   Saunders, C ^b   Ramsay, R G ^c   Thompson, E W ^a,c,d  

^a ST VINCENT'S INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^c UNIVERSITY OF MELBOURNE   (Australia)

^d QUEENSLAND UNIVERSITY OF TECHNOLOGY   (Australia)

Author keywords

Breast cancer; c Myb; Chronic inflammation; COX 2; EMT; HIF1

Indexed keywords

ACETYLSALICYLIC ACID; CYCLOOXYGENASE 2; ESTROGEN RECEPTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; PROTEIN C MYB; HIF1A PROTEIN, HUMAN;

BREAST CANCER; BREAST CARCINOGENESIS; CANCER GROWTH; CANCER RISK; CANCER SURVIVAL; CELL PROLIFERATION; CHRONIC INFLAMMATION; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; IN VITRO STUDY; METASTASIS; NEOPLASM; NONHUMAN; OBESITY; POSTPARTUM INVOLUTION; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PUERPERIUM; REVIEW; RISK REDUCTION; SIGNAL TRANSDUCTION; TUMOR INVASION; TUMOR MICROENVIRONMENT; BREAST TUMOR; CHRONIC DISEASE; FEMALE; INFLAMMATION; METABOLISM; MORTALITY; PATHOLOGY;

BREAST NEOPLASMS; CHRONIC DISEASE; CYCLOOXYGENASE 2; EPITHELIAL-MESENCHYMAL TRANSITION; FEMALE; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; INFLAMMATION; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; PROTO-ONCOGENE PROTEINS C-MYB; SIGNAL TRANSDUCTION;

EID: 84947035057     PISSN: 10833021     EISSN: 15737039     Source Type: Journal    
DOI: 10.1007/s10911-015-9333-4     Document Type: Review

References (147)

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.
2. Hemler ME, Lands WE. Biosynthesis of prostaglandins. Lipids. 1977;12(7):591–5.
3. Kam PC, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role. Anaesthesia. 2000;55(5):442–9.
4. Simmons DL. Variants of cyclooxygenase-1 and their roles in medicine. Thromb Res. 2003;110(5–6):265–8.
5. Roos KL, Simmons DL. Cyclooxygenase variants: the role of alternative splicing. Biochem Biophys Res Commun. 2005;338(1):62–9.
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.
7. Harris RE, Casto BC, Harris ZM. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol. 2014;5(4):677–92.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
23. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31(5):986–1000.
24. Ghosh AK. Regulation by prostaglandin E2 and histamine of angiogenesis in inflammatory granulation tissue. Yakugaku Zasshi. 2003;123(5):295–303.
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.
26. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
46. Angelo LS, Kurzrock R. Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res. 2007;13(10):2825–30.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
85. Ives A, Saunders C, Harvey J, Semmens J. The histopathological profile of gestational breast cancer. In European Breast Cancer Conference 2006: Nice, France.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
112. Ramsay RG, Gonda TJ. MYB function in normal and cancer cells. Nat Rev Cancer. 2008;8(7):523–34.
113. Ernst M, Ramsay RG. Colorectal cancer mouse models: integrating inflammation and the stroma. J Gastroenterol Hepatol. 2012;27(1):39–50.
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.
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.
116. Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007;67(8):3496–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
127. Wells A, Griffith L, Wells JZ, Taylor DP. The dormancy dilemma: quiescence versus balanced proliferation. Cancer Res. 2013;73(13):3811–6.
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.
129. Thompson MA, Ramsay RG. Myb: an old oncoprotein with new roles. Bioessays. 1995;17(4):341–50.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.