CYP3A4*1B variant allele and the risk of breast cancer

Purpose CYP3A4 is one of the many cytochrome P450 enzymes involved in the metabolic hydroxylation of 17β-estradiol, but it has the highest 2-hydroxylation activity of the P450 class III enzymes. It has been postulated that 2-hydroxylated estradiol is anticarcinogenic. We hypothesized that women with the variant allele, especially those who are active smokers have an enriched concentration of 2-hydroxylated estradiol, would be at lower risk of developing breast cancer. Methods We used a case-control design to assess the relationship between the CYP3A4*1B allele and breast cancer risk. We identified 168 cases of invasive breast cancer and 116 controls from eight towns in Cape Cod, Massachusetts, between 1987 and 1993. We genotyped cases and controls to identify those with the CYP3A4*1B variant allele. We collected information on exposure to tobacco smoke and other breast cancer risk factors using structured interviews. Results Women with one or more copies of the CYP3A4*1B variant allele were at reduced risk of developing breast cancer (adjusted odds ratio [AOR] = 0.4, 95% confidence interval [CI]: 0.2–1.1). The CYP3A4*1B variant allele was more protective among ever-active smokers (AOR = 0.2, 95% CI: 0.06–1.0) than among never-active smokers (AOR = 0.7, 95% CI: 0.2–2.8). Conclusion We provide evidence to support a protective association between the CYP3A4*1B variant allele and breast cancer risk, a finding consistent with accumulating evidence that enhanced 2-hydroxylation of 17β-estradiol protects against incident breast cancer.