Cancer Chemoprevention by Cyclooxygenase 2 (COX-2) Blockade

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: Induction Of Cox-2mentioning

confidence: 99%

mentioning

confidence: 99%

Cyclooxygenase-2 and the inflammogenesis of breast cancer

Casto

2014

WJCO

154

125

Cancer Epidemiology, Biomarkers &Amp; Prevention

“…Experimental studies have reported a protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, against mammary carcinogenesis (1-3), and accumulating evidence from both casecontrol and cohort studies suggests that use of NSAIDs may be associated with a modest decreased risk of breast cancer in women (4)(5)(6)(7)(8)(9)(10). However, findings are mixed (11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Nonsteroidal Anti-inflammatory Drug Use and Serum Total Estradiol in Postmenopausal Women

Hudson¹,

Gierach

Modugno³

et al. 2008

Laboratory and epidemiologic evidence suggest that nonsteroidal anti-inflammatory drug (NSAID) use may be inversely related to the risk of breast cancer; however, the mechanism by which NSAIDs may protect against the development of this disease is uncertain. The objective of this observational study was to assess the relationship between current NSAID use and endogenous estradiol levels, an established breast cancer risk factor. To evaluate this aim, we conducted a cross-sectional investigation among 260 postmenopausal women who were not recently exposed to exogenous hormones. Information on current NSAID use (aspirin, cyclooxygenase-2 inhibitors, and other NSAIDs combined) was collected using a questionnaire at the time of blood draw. Estradiol was quantified in serum by radioimmunoassay. General linear models were used to evaluate the association between NSAID use and serum total estradiol. The age-adjusted and body mass index -adjusted geometric mean serum estradiol concentration among NSAID users (n = 124) was significantly lower than nonusers of NSAIDs (n = 136; 17.8 versus 21.3 pmol/L; P = 0.03). Further adjustment for additional potential confounding factors did not substantially alter estimates (17.7 versus 21.2 pmol/L; P = 0.03). To our knowledge, this report is the first to examine the relationship between NSAID use and serum estradiol in postmenopausal women. These cross-sectional findings suggest that NSAID use may be associated with lower circulating estradiol levels, potentially representing one mechanism through which NSAIDs exert protective effects on breast cancer.

“…Further studies are required to elucidate the dosage, duration, side effects and cost-effectiveness of such agents in the chemoprevention of lung cancer (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

Ibuprofen and fatal lung cancer: A brief report of the prospective results from the Third National Health and Nutrition Examination Survey (NHANES III)

Bittoni

Carbone

Molecular and Clinical Oncology

2017

Self Cite

Abstract. Chronic inflammation appears to increase the risk of lung cancer and, reciprocally, agents that reduce inflammation have been found to reduce this risk. However, few prospective studies have assessed whether there exists an association between lung cancer and the use of non-steroidal anti-inflammatory drugs (NSAIDs). In the present study, the association between fatal lung cancer and NSAIDs was investigated using cohort data from the Third National Health and Nutrition Examination Study (NHANES III). Baseline data were collected on smoking, NSAID use and other lifestyle factors for 10,735 participants during 1988-1994, with cause-specific mortality status ascertained through probabilistic record matching based on the National Death Index until 2006. Cox proportional hazards regression models were conducted to estimate hazard ratios (HRs) and confidence intervals (CIs) for NSAID use and death from lung cancer, controlling for current smoking and other covariates. During the 18 years of follow-up, 269 participants succumbed to lung cancer, of whom 252 (93.6%) reported a history of cigarette smoking. Since all but 17 of the 269 fatal lung cancer cases occurred among current or former smokers, estimates of NSAID effects were ascertained from a sub-cohort of 5,882 individuals who reported a history of past or current cigarette smoking. Multivariate regression models revealed that regular use of ibuprofen resulted in a 48% reduced risk of lung cancer mortality (HR= 0.52, 95% CI: 0.33-0.82, P<0.01). The main effects of other compounds tested, such as aspirin or acetaminophen, were not statistically significant. Our results suggest that high-risk subgroups of smokers may benefit from the regular use of specific NSAIDs, which may prove to be a useful strategy for lung cancer prevention.