There is growing evidence that germline mutations in certain genes influence cancer susceptibility, tumor evolution, as well as clinical outcomes. Identification of a disease-causing genetic variant enables testing and diagnosis of at-risk individuals. For breast cancer, several genes such as BRCA1, BRCA2, PALB2, ATM, and CHEK2 act as high- to moderate-penetrance cancer susceptibility genes. Genotyping of these genes informs genetic risk assessment and counseling, as well as treatment and management decisions in the case of high-penetrance genes. TGFBR1*6A (rs11466445) is a common variant of the TGF-β receptor type I (TGFBR1) that has a global minor allelic frequency (MAF) of 0.051 according to the 1000 Genomes Project Consortium. It is emerging as a high frequency, low penetrance tumor susceptibility allele associated with increased cancer risk among several cancer types. The TGFBR1*6A allele has been associated with increased breast cancer risk in women, OR 1.15 (95% CI 1.01–1.31). Functionally, TGFBR1*6A promotes breast cancer cell proliferation, migration, and invasion through the regulation of the ERK pathway and Rho-GTP activation. This review discusses current findings on the genetic, functional, and mechanistic associations between TGFBR1*6A and breast cancer risk and proposes future directions as it relates to genetic association studies and mechanisms of action for tumor growth, metastasis, and immune suppression.

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TGFBR1*6A (rs1466445) is a common low penetrance tumor susceptibility allele with a minor allelic frequency of 0.051. Several meta-analyses show that TGFBR1*6A is associated with breast cancer risk with an OR ranging from 1.15 to 1.30. We developed a novel knockin mouse model of TGFBR1*6A to study mammary cancer development and progression in MMTVneu mice. Here we show that TGFBR1*6A accelerates tumor onset, increases the percentage of mice with tumors, and the percentage of mice with multiple tumors. Age at tumor onset, tumor formation, and tumor multiplicity depend on TGFBR1*6A allelic dosage. Functional characterization shows that TGFBR1*6A confers higher tumor growth and clonogenicity and enhances G0/G1 cell cycle progression through downregulation of p27. These findings establish TGFBR1*6A as a potent modifier of breast cancer development and progression, which may affect more than 10% of patients with breast cancer.

Dense fibrosis of the breast as assessed by mammography may be associated with early disease diagnosis. Radiation-induced fibrosis occurs in a large fraction of patients following breast conserving therapy and may be modified by genetic susceptibility. TGFBR1*6A is a high frequency, low penetrance TGFBR1 hypomorphic variant, which is associated with breast cancer risk. Here we show an association of TGFBR1*6A with breast cancer tissue fibrosis in mice and in patients with HER2-positive breast cancer.