Abstract
Endogenously formed prostacyclin (PGI2) and synthetic PGI2 analogues have recently been shown to regulate cell survival in various cell lines. To elucidate the significance of PGI2 in human breast cancer, we performed immunohistochemistry to analyze expression of prostacyclin-synthase (PGIS) in 248 human breast cancer specimens obtained from surgical pathology files. We examined patients' 10-year survival retrospectively by sending a questionnaire to their general practitioners and performed univariate analysis to determine whether PGIS expression correlated with patient survival. Lastly, the effects of PGI2 and its analogues on cell death were examined in a human breast cancer cell line (MCF-7) and a human T-cell leukemia cell line (CCRF-CEM). PGIS expression was observed in tumor cells in 48.7% of samples and was associated with a statistically significant reduction in 10-year survival (P = 0.038; n = 193). Transient transfection of PGIS into MCF-7 cells exposed to sulindac increased cell viability by 50% and exposure to carbaprostacyclin protected against sulindac sulfone induced apoptosis in CCRF-CEM cells. Expression of PGIS is correlated with a reduced patient survival and protects against cell death in vitro, suggesting that PGIS is a potential therapeutic target in breast cancer.
Highlights
Epidemiological studies have shown that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of a range of epitheliumderived malignancies [1]
NSAIDs inhibit the enzymatic activity of cyclooxygenase (COX), the enzyme that provides prostaglandin H2 and is considered to provide the rate-limiting step during prostanoid synthesis [2]
Given that sulindac inhibits prostaglandinproduction, and PGI2 formation, we assume that PGI2 generated during the first 24 hours after transfection and prior to the addition of sulindac rendered the cells resistant to the adverse effects of sulindac
Summary
Epidemiological studies have shown that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of a range of epitheliumderived malignancies [1]. Two isoforms exist: the constitutive COX-1 and the inducible COX-2 Specific inhibitors of the latter ( called coxibs or COX-2 selective NSAIDs) have been developed because gastrointestinal side-effects of NSAIDs are thought to result from COX-1 inhibition. As COX-2 is expressed in the majority of human cancers, including breast cancer [3, 4], COX-2 selective inhibitors (coxibs) next to COX-2 unselective ones (conventional NSAID) are tested for their antitumor activity. Mediators of Inflammation incubation of NSAIDs with human breast cancer cell lines has been shown to induce apoptosis [11]
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