Polymorphisms of the TGF-β pathway and breast cancer risk: A case control study

Abstract

9548 Background: Recent studies indicate that variants coding for ligand and receptor within the Transforming Growth Factor Beta (TGF-β) signaling pathway may modify breast cancer risk. A common genotype that increases circulating TGF-β levels, TGFB1*CC, is associated with decreased breast cancer risk. Conversely, a common variant that results in decreased TGF-β mediated growth inhibition, TGFBR1*6A, is associated with increased breast cancer risk. Objective: To examine breast cancer risk associated with TGF-β signaling pathway as assessed by two common and functionally relevant variants. Methods: Peripheral blood DNA from 660 consecutive breast cancer cases from Memorial Sloan-Kettering Cancer Center and 880 healthy females from New York. Estrogen receptor (ER), progesterone receptor (PR) status as well as disease stage were available for 152 patients. Main Outcome Measures: Breast cancer risk as assessed by combined TGFB1 and TGFBR1 genotyping. Breast cancer risk for TGFB1*CC carriers. Breast cancer risk for TGFBR1*6A carriers. Results: The O.R. for individuals with the lowest expected TGF-β signaling level (TGFB1*CT or TGFB1*TT and TGFBR1*6A) was 1.69 (1.08–2.66) when compared with individuals with the highest expected TGF-signaling levels (TGFB1*CC and TGFBR1/TGFBR1). TGFBR1*6A was associated with a significantly increased risk for breast cancer O.R. 1.46 (1.04–2.06) but TGFB1*CC was not associated with any modified breast cancer risk O.R. 0.89 (0.63–1.21). TGFBR1*6A effect was most pronounced among women diagnosed after the age of 50: O.R. 2.20 (1.25–3.87). Conclusions: Our findings suggest that common variants of the TGF-β signaling pathway are potent modulators of breast cancer risk. No significant financial relationships to disclose.