FOXA1: master of steroid receptor function in cancer

Abstract

FOXA transcription factors are potent, context-specific mediators of development that hold specialized functions in hormone-dependent tissues. Over the last several years, FOXA1 has emerged as a critical mediator of nuclear steroid receptor signalling, manifest at least in part through regulation of androgen receptor and oestrogen receptor activity. Recent findings point towards a major role for FOXA1 in modulating nuclear steroid receptor activity in breast and prostate cancer, and suggest that FOXA1 may significantly contribute to pro-tumourigenic phenotypes. The present review article will focus on the mechanisms, consequence, and clinical relevance of FOXA1-mediated steroid nuclear receptor signalling in human malignancy.

Figure 1

Converging pathways of FOXA1 on AR-regulated growth of MDA-MB-453. The mechanisms through which AR regulates growth of molecular apocrine cancer cells described by Ni et al and Robinson et al are summarized. Both studies utilized gene expression arrays coupled to AR/FOXA1 ChIP sequencing to identify novel mechanisms through which AR functions in this cell type. Briefly, Robinson et al (2011) uncovered an ERα-like signature regulated by AR. Only in the presence of FOXA1 was AR able to bind to oestrogen-regulated genes (ERG), and induce a gene set classically regulated by ERα, responsible for growth. Concurrent studies by Ni et al (2011) identified a FOXA1/AR-dependent induction of the WNT7B gene. Subsequent signalling through the Wnt pathway induced nuclear accumulation of β-catenin, association with AR, and localization to the HER3 regulatory gene locus. Here, they describe the growth effects of AR signalling as dependent on HER3 induction and signalling through the AKT pathway.

Figure 2

Three categories of AR binding sites in prostate cancer cells. The three categories of AR binding sites that have been described by Wang et al (2011) and Sahu et al (2011) in the LNCaP cell line are highlighted. The presence of high FOXA1 directs AR to sites that are enriched for both forkhead motifs as well as AREs, while low levels of FOXA1 reveal novel AR binding sites that lack neighbouring FKH motifs but maintain ARE enrichment. Additionally, sites exist in the genome where FOXA1 is dispensable for AR binding and transcriptional induction. The number of binding sites indicated below each class are representative of the Sahu data set.