Association between the T29 -> C polymorphism in the transforming growth factor beta 1 gene and breast cancer among elderly white women the study of osteoporotic fractures

Context Transgenic animal experiments suggest that increased expression of transforming growth factor beta1 (TGF-beta1) is protective against early tu mor development, particularly in breast cancer. A T -->C (thymine to cytosi ne) transition in the 29th nucleotide in the coding sequence results in a l eucine to proline substitution at the 10th amino acid and is associated wit h increased serum levels of TGF-beta1. Objective To determine whether an association exists between this TGF-beta1 polymorphism and breast cancer risk. Design, Setting, and Participants The Study of Osteoporotic Fractures, a pr ospective cohort study of white, community-dwelling women aged 65 years or older who were recruited at 4 US centers between 1986 and 1988. Three thous and seventy-five women who provided sufficient clinical information, buffy coat samples, and adequate consent for genotyping are included in this anal ysis. Main Outcome Measure Breast cancer cases during a mean (SD) follow-up of 9. 3 (1.9) years, verified by medical chart review and compared by genotype. Results Risk of breast cancer was similar in the 1124 women with the T/T ge notype (56 cases; 5.4 per 1000 person-years) and the 1493 women with the T/ C genotype (80 cases; 5.8 per 1000 person-years) but was significantly lowe r (P=.01) in the 458 women with the C/C genotype (10 cases; 2.3 per 1000 pe rson-years). In analyses that adjusted for age, age at menarche, age at men opause, estrogen use, parity, body mass index, and bone mineral density, wo men with the C/C genotype had a significantly lower risk of developing brea st cancer compared with women with the T/T or T/C genotype (hazard ratio [H R], 0.36; 95% confidence interval [CI], 0.17-0.75). There was no significan t difference between the risk for women with the T/C genotype compared with women with the T/T genotype (adjusted HR, 1.04; 95% CI, 0.73-1.48). Conclusions Our findings suggest that TGF-beta1 genotype is associated with risk of breast cancer in white women aged 65 years or older. Because the T allele is the common variant and confers an increased risk, it may be asso ciated with a large proportion of breast cancer cases.