TGFBR1*6A as a modifier of breast cancer risk and progression: advances and future prospects

Abstract

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.

Fig. 1. TGFBR1 and TGFBR1*6A gene and protein sequences.

Sequence analyses reveal nine (9) GCG/alanine repeats within nucleotides 42–119 of the TGFBR1 signal sequence. TGFBR1*6A variant has six (6) GCG/alanine repeats in its signal sequence (Pasche, Luo et al. 1998, Pasche, Kolachana et al. 1999).

Fig. 2. Studies investigating TGFBR1*6A association with breast cancer risk.

Forest plot showing the number of subjects and odds ratios of a Case-control studies, and b Meta-analyses associating TGFBR1*6A to breast cancer risk. Plot a includes only case/control studies that are in Hardy–Weinberg equilibrium. CI confidence interval, ɪ dominant association (p ≤ 0.01), ‡ additive association (p ≤ 0.05), † allelic association (p ≤ 0.05).

Fig. 3. Schematic showing the role of TGFBR1*6A signal peptide.

a TGFBR1*6A protein translation and processing, the TGFBR1*6A signal peptide is cleaved between Ala30 and Leu31, whereas the wild-type TGFBR1 is cleaved between Ala33 and Leu34. Both TGFBR1*6A and TGFBR1 wild-type exhibit similar binding affinity to TGFB ligand and stability (half-life). The TGFBR1*6A signal peptide also demonstrates similar protein targeting and translocation functions as the wild-type. b TGFBR1*6A intracellular signaling, TGFBR1*6A maintains intact TGF-β signaling to induce growth and migration in breast cancer cells. It shows similar TGF-β signaling as wild-type TGFBR1 but enhances phosphorylation of ERK1/2 to induce its tumor-promoting effects.