TGFBR1*6A enhances breast cancer development through downregulation of p27

Abstract 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.