Cytochrome P450 polymorphisms as risk factors for steroid hormone-related cancers

The development of cancers of the breast, endometrium, ovaries and possibly prostate is modulated by steroid hormones. Many steroids and environmental carcinogens are subject to cytochrome P450 (P450)-mediated metabolism that generates reactive metabolites and modulates steroid potency, thereby influencing tumor initiation and promotion respectively. These pathways, which are modulated by polymorphisms in P450 genes, are therefore likely to play an important role in the etiology of hormone-related cancers. Several groups have evaluated genotypes of xenobiotic- and steroid-metabolizing P450 enzymes as risk factors for hormone-related cancers. Polymorphisms in P450s that are specifically involved in the metabolism of steroids appear to be single risk factors. The situation is less clear for xenobiotic-metabolizing P450s. For these genes, only combined genotypes of several P450s or combined genotypes of P450s together with other enzymes have been clearly correlated with disease frequency. Success in identifying the appropriate combination of candidate genes requires a thorough knowledge of the metabolic pathways and enzyme systems that control the initial stages of carcinogenesis, as will be illustrated in this review.