TheCYP3A4*1Bpolymorphism has no functional significance and is not associated with risk of breast or ovarian cancer

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CYP3A4 is involved in the metabolism of endogenous steroids, and an allelic variant,CYP3A4*1B, consisting of an A to G polymorphism within the 5'-flanking region termed the nifedipine-specific response element (NFSE) has been associated with high grade and advanced stage of prostate cancers. Because steroid hormone exposure is known to influence breast and ovarian cancer risk, we conducted case–control studies to assess the relationship betweenCYP3A4*1Band risk of breast or ovarian cancer.CYP3A4NFSE genotype was determined in 951 breast cancer cases and 500 controls frequency matched for age and 488 ovarian cancer cases and 276 controls of similar age distribution. Case–control analyses and comparisons of genotype distributions were conducted by unconditional logistic regression. In addition, the functional significance of theCYP3A4*1Bpolymorphism was assessed by analysis ofCYP3A4-reporter gene constructs transiently transfected into liver-derived cell lines and primary cultures of well-differentiated rat hepatocytes. The GG genotype was rare in all groups (0–0.4%). There was no risk of cancer associated with the AG/GG genotypes combined, with an OR (95% CI) of 0.86 (0.54–1.33) for breast cancer (P= 0.5), and 1.51 (0.80–2.89) for ovarian cancer (P= 0.2). Analysis ofCYP3A4-luciferase constructs showed thatCYP3A4*1Bdid not consistently affect reporter gene activity. Our data suggest that theCYP3A4*1Bpolymorphism is not associated with risk of breast or ovarian cancer. In support of this negative finding, in-vitro functional studies indicate that NFSE genotype is not a critical factor in the transcriptional activity of theCYP3A45'-flanking region, and is thus unlikely to modulate CYP3A4-mediated metabolism of steroids.

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