TGF-B signaling pathway, ER-alpha and the heterogeneity of breast cancer risk among Hispanic and non-Hispanic white women

Many risk factors for breast cancer differ between race/ethnic groups. Few studies have included Hispanic women: a genetically admixed population that differs from other ethnic groups for breast cancer incidence, survival, and tumor phenotype. The objective of this study was to determine if genetic variation in ERalpha and TGF-beta signaling genes (TGF-beta1, TGF-betaRI, RUNX1, RUNX2, RUNX3) is associated with breast cancer risk, and if these associations differ between Hispanic and non-Hispanic white women (NHW).;Data from The Breast Cancer Health Disparities (BCHD) study were used. BCHD is a multi-site consortium including two case-control studies within the U.S. and one in Mexico. A total of 3,524 cases (NHW=1,431; Hispanic=2,093) and 4,209 population-based controls (NHW=1,599; Hispanic=2,610) had available DNA. In-person interviews collected information on non-genetic risk factors. Single nucleotide polymorphisms (SNPs) in TGF-beta, RUNX and ERalpha genes were determined using an Illumina platform and PCR. Associations with breast cancer risk were evaluated using multivariable logistic regression, adjusting for study site, age, and Native American genetic ancestry.;Associations with breast cancer phenotypes (ER/PR status) were also evaluated and a genetic risk score (GRS) was calculated to determine the cumulative effect of selected SNPs.;Two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG=1.15 95% CI 1.04-1.26) and TGF-beta1 (rs4803455 ORCA/AA=0.89 95% CI 0.81-0.98). RUNX3 (rs906296) was specifically associated with risk in pre-menopausal women (p=0.002) and in those with moderate to high Native American ancestry. There was a significant interaction between Native American ancestry and RUNX1 (rs7279383, p=0.04). Four RUNX SNPs were associated with an increased risk of ER-/PR- (n=3) and ER-/PR+ (n=1) tumors. A GRS including 6 SNPs (range=0-10 alleles) across ERalpha and TGF-beta signaling genes was positively associated with overall risk (per allele OR=1.14 95% CI 1.04-1.25), as well as ER+, but not ER- tumors.;These results suggest that genetic variation in these genes may explain the greater likelihood in Hispanic women for premenopausal, ER- breast cancer. This is also the first population-based observational study to evaluate crosstalk between TGF-beta and ERalpha signaling pathways. The biological significance of these genes in breast cancer etiology is strongly supported and the results warrant confirmation in future studies.