A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk

Biological and epidemiological data suggest that progesterone has an important role in mammary tumorigenesis. Because the effects of progesterone require the progesterone receptor (PGR), which exists in two isoforms, PR-A and PR-B, we sought to determine whether the functional polymorphism, +331 G/A, which causes an increase in the expression of the hPR-B isoform, is related to breast cancer risk. Using a nested case-control study design within the Nurses' Health Study cohort, we genotyped 990 cases and 1,364 controls and observed a statistically significant increased risk of breast cancer among carriers of the +331 A allele (odds ratio, 1.33; 95% confidence interval, 1.01-1.74) compared with subjects with the GG genotype. We also observed a potential interaction between genotype and body mass index (BMI) among postmenopausal women, with the highest risk (odds ratio, 2.30; 95% confidence interval, 1.02-5.21) among obese women (BMI ≥30 kg/m²) with the GA or AA genotype compared with lean (BMI <25 kg/m²) women with the GG genotype. Our findings suggest that the increased production of hPR-B by the +331 G/A polymorphism may predispose women to breast cancer development through increased hPR-B-dependent stimulation of mammary cell growth.