FOXA1 Protein Expression in ER+ and ER− Breast Cancer in Relation to Parity and Breastfeeding in Black and White Women

Abstract

Background: Forkhead box protein A1 (FOXA1) promotes luminal differentiation, and hypermethylation of the gene can be a mechanism of developing estrogen receptor–negative (ER−) breast cancer. We examined FOXA1 in breast tumor and adjacent normal tissue in relation to reproductive factors, particularly higher parity and no breastfeeding, that are associated with ER− tumors. Methods: We performed IHC for FOXA1 in breast tumors (n = 1,329) and adjacent normal tissues (n = 298) in the Women's Circle of Health Study (949 Blacks and 380 Whites). Protein expression levels were summarized by histology (H) scores. Generalized linear models were used to assess FOXA1 protein expression in relation to reproductive factors by ER status. Results: ER-positive (ER+) versus ER− tumors had higher FOXA1 protein expression (P < 0.001). FOXA1 expression was higher in tumor versus paired adjacent normal tissue in women with ER+ or non-triple–negative cancer (both P < 0.001), but not in those with ER− or triple-negative cancer. Higher number of births (1, 2, and 3+) was associated with lower FOXA1 protein expression in ER+ tumors [differences in H score, or β = −8.5; 95% confidence interval (CI), −15.1 to −2.0], particularly among parous women who never breastfed (β = −10.4; 95% CI, −19.7 to −1.0), but not among those who breastfed (β = −7.5; 95% CI, −16.9 to 1.8). The associations for ER− tumors were similar, although they were not statistically significant. Conclusions: In this tumor-based study, higher parity was associated with lower FOXA1 expression in ER+ tumors, and breastfeeding may ameliorate the influence. Impact: These findings contribute to our understanding of FOXA1 methylation and breast cancer etiology.

Evaluation of the Expression Level of Some Coding and Non-coding Genes in Breast Cancer Samples Based on Bioinformatics and Laboratory Studies

“…Forkhead box A1 plays a role in enhancing luminal differentiation, gene methylation, and the overexpression of the ER gene in BC. Similar to our investigation, several studies have reported elevated levels of FOXA1 gene and protein expression in BC compared to normal mucosa, suggesting its potential as a diagnostic biomarker (20)(21)(22)(23)(24)(25). Previous studies have Int J Cancer Manag.…”

Genome-Wide Estrogen Receptor Activity in Breast Cancer

“…This could be due to changes in ER interaction partners or changes to factors which influence ER binding. For example, both FOXA1 and GATA3 were reported to show higher expression in tumor versus normal tissue ( 160 , 161 ). Increased ER binding also suggests that the transition to tumorigenesis may be characterized by an overall increase in genome accessibility, thereby exposing more potential TF binding sites.…”

DNA methylation differences in noncoding regions in ER negative breast tumors between Black and White women

“…We previously reported a FOXA1 raDML (cg04932551), located in the gene body, which is annotated as a poised promoter. This site was hypermethylated in tumors from Black versus White women, and its methylation was inversely associated with FOXA1 RNA and protein expression in ER- tumors among Black women ( 12 , 51 ). We further found that methylation and expression of FOXA1 is associated with parity and breastfeeding, suggesting a potential mechanism that links these reproductive exposures with ER- breast cancer among Black women ( 12 ).…”