Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness

Casto

2014

WJCO

154

125

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2 (COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following: (1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis; (2) essential features of mammary carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2 (PGE-2) biosynthesis; (3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis; (4) extrahepatic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and (5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer". Key words: Breast Cancer; Cyclooxygenase-2; Nonsteroidal anti-inflammatory drugs; Inflammogenesis; Estrogen; Aromatase Core tip: Mammary carcinogenesis often evolves as a series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of cyclooxygenase-2 (COX-2) and the prostaglandin cascade; reciprocally, agents that block COX-2 have significant value in the chemoprevention and therapy of breast cancer.Harris RE, Casto BC, Harris ZM. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol 2014; 5(4): 677-692 Available from: URL: http://www.wjgnet.com/2218-4333/full/v5/ i4/677.htm DOI: http://dx.doi.org/10.5306/wjco.v5.i4.677 INTRODUCTIONMore than a century ago, Virchow et al [1,2] chronic inflammation leads to cancer development by increasing cellular proliferation [3] . Various models of carcinogenesis have been proposed involving inflammatory stimuli and mediators of wound healing [4][5][6] . The recent discovery of the inducible cyclooxygenase-2 (COX-2) gene has rekindled interest in the causal link between inflammation and cancer, and various models of carcinogenesis have been proposed involving inflammatory stimuli and COX-2 expression [7][8][9][10] . The current review synthesizes and interprets the accumulating body of evidence supporting COX-2 driven inflammogenesis as a ge...

Section: Mitogenesismentioning

confidence: 86%

mentioning

confidence: 99%

Cyclooxygenase-2 and the inflammogenesis of breast cancer

Casto

2014

WJCO

154

125

J Mammary Gland Biol Neoplasia

“…Thus, Celecoxib was found to be effective in upregulating E-cadherin thus reversing the EMT in cell lines derived from head and neck squamous cancer, colon cancer, gastric cancer and breast cancer [101][102][103][104]. Another COX-2 inhibitor, Etodolac, had a similar effect in bladder cancer cell lines, where EMT reversal was also seen in vivo in xenografts of the human bladder cancer cell line T24 [105].…”

Section: Cox-2 Is Associated With Breast Cancer Invasion Via Emtmentioning

confidence: 93%

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

Hugo

Saunders

Ramsay

et al. 2015

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.

Journal of Biological Chemistry

“…Activation of S1PR2-COX-2 is a key enzyme involved in production of prostaglandins and has been implicated in various cell transformations including cholangiocytes (21)(22)(23)(24)(25). Previous studies reported that CBAs induced COX-2 expression and promoted growth in human CCA cells in culture (15,16).…”

Section: Tca Induces Cox-2 Expression and Chronic Inflammation Viamentioning

confidence: 99%

Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line

Liu

Xiao

et al. 2015

Background: Cyclooxygenase-2 (COX-2) and sphingosine 1-phosphate receptor 2 (S1PR2) are highly expressed in human cholangiocarcinoma (CCA) and taurocholate (TCA) promotes CCA cell growth via S1PR2. Results: TCA-mediated activation of S1PR2 contributed to COX-2 expression and CCA cell growth. Conclusion: S1PR2 plays a critical role in TCA-induced COX-2 expression and CCA growth. Significance: S1PR2 represents a novel therapeutic target for CCA.