Modulation of breast cancer risk by nonsteroidal anti-inflammatory drugs.

their fi ndings on NSAID use and breast cancer risk? The answer lies in an appreciation of the likely mechanisms of NSAID-mediated breast cancer suppression. COX enzymes, the primary molecular targets of NSAIDs, synthesize prostaglandins (PGs) from arachidonic acid (13 , 14). COX-1 is normally expressed constitutively, whereas COX-2 is an early-response gene whose expression is increased in response to growth factors, oncogenes, and cytokines and is a key component of the infl ammatory response (5 , 14 , 15). Transgenic overexpression of COX-2 induces mammary tumor formation in mice (16); activation of COX/PG signaling has multiple procarcinogenic consequences, including regulation of proliferation, apoptosis, angiogenesis, invasion , and immune responsiveness (5 , 14). Patterns of COX-2 overex-pression differ substantially between breast and colorectal neoplasia. Nonsteroidal anti-inflammatory drugs (NSAIDs) clearly reduce the risk of human colorectal neoplasia in epidemiological and prospective randomized clinical studies of aspirin and nonaspirin NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibi-tors, or coxibs (1 – 3). In contrast, the epidemiological and clinical data on NSAIDs in reducing breast cancer risk are not consistent. This inconsistency is likely attributable to contrasting expression patterns of COX-2, a key target of NSAIDs, in breast and colon neoplasia (4 , 5), and to differing activities of individual NSAIDs (which have varying selectivity for COX-2 vs COX-1), including a potentially selective impact of certain NSAIDs on hormone receptor – positive breast tumors. In this issue of the Journal, Takkouche et al. (6) report an extensive meta-analysis (involving 38 studies) supporting an inverse association between NSAID use and risk of breast cancer. They found a statistically signifi cant reduction in breast cancer risk associated with use of any NSAID (relative risk [RR] = 0.88, 95% confi dence interval [CI] = 0.84 to 0.93) and similar associations for aspirin (RR = 0.87, 95% CI = 0.82 to 0.92) and ibuprofen (RR = 0.79, 95% CI = 0.64 to 0.97). They found no evidence of a dose – response relationship, and some studies indicated that coxibs were also associated with a lower risk of breast cancer (7 , 8). This large-scale meta-analysis is consistent with several smaller meta-analyses (9 – 12). Furthermore, NSAIDs can prevent experimental breast cancer in numerous rodent models (4 , 5). Why then do individual observational and clinical studies vary substantially in See " Funding " following " References. "