FOXA1 is an independent prognostic marker for ER-positive breast cancer

Abstract

Forkhead box protein A1 (FOXA1) is a "pioneer factor" that plays a role in controlling nearly 50% of estrogen receptor target genes. FOXA1 expression correlates with estrogen receptor (ER)-positivity especially in luminal subtype A breast cancers. The aim of this study was to investigate the precise role of FOXA1 in breast cancer using a large population-based cohort. Nuclear expression of FOXA1 was analyzed in a tissue microarray of 4,444 invasive breast cancer cases using immunohistochemistry and correlated with clinicopathologic variables using previously described methods and cutoff points. The entire cohort was equally divided into a training and validation set. All survival analyses were performed using a previously defined cutoff (3) for validation. Additional X-tile analysis performed to analyze prognostic effects of low and high FOXA1 levels identified 24 as a cutoff. Bonferroni-Holmes test was used as appropriate. FOXA1 expression significantly correlated positively with markers of good prognosis or ER-positivity, and negatively with tumor size, tumor grade, nodal status, Ki67, HER2 expression, and basal subtype (each P value <0.0001). In both survival analyses, FOXA1 was a significant predictor of breast cancer-specific survival (P < 0.0001) and relapse-free survival (P < 0.0001). FOXA1 was also an independent predictor of breast cancer-specific survival at 10 years using both cutoffs. Among the ER-positive subgroup treated with tamoxifen, FOXA1 was an independent prognostic marker using the 24 cutoff (P = 0.030). FOXA1 is a significant marker of good prognosis in breast cancer; it also identifies a subset of ER-positive tamoxifen treated patients at low risk of recurrence.

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

“…In this process, several pioneer factors can dynamically modulate chromatin openness in breast cancer cells (35). Among the known pioneer factors contributing to the estrogen response, FOXA1, GATA3, and PBX1 seem to play a role in ET resistance (36)(37)(38). In the HBCx34 TamR tumor, FOXA1 and GATA3 expression was increased, supporting the possibility of an epigenetic origin of the generalized ET resistance in this tumor.…”

miR-1290 and its potential targets are associated with characteristics of estrogen receptor α-positive breast cancer

“…It was also reported that six miRNAs, including miR-1290, were upregulated in drug-sensitive cells following Y-Box protein 1 inhibition, but no differences in miRNA expression could be detected in multidrug-resistant gastric carcinoma cells (Belian et al 2010). FOXA1, a forkhead family transcription factor, has been reported to be expressed predominantly in luminal A breast cancer with favorable prognosis (Badve et al 2007, Mehta et al 2012. Hurtado et al recently reported that FOXA1 creates an open conformation at ER-binding sites and that ER can bind and activate target gene expression in the presence of estrogen.…”

Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review)

“…Among these, the expression of FOXA1 was positively correlated with ER-positivity, particularly luminal A type ER-positivity, and negatively correlated with tumor size, tumor grade, nodal status, the expression of Ki-67 and HER2 and basal-like subtype of breast cancer (31). A previous study reported that the expression of FOXA1 was positively correlated with ER + and PR + status, but inversely correlated with nuclear grade and the Ki-67 index, suggesting the therapeutic potentials of FOXA1 targeting (73).…”