FOXA1: a transcription factor with parallel functions in development and cancer

Abstract

When aberrant, factors critical for organ morphogenesis are also commonly involved in disease progression. FOXA1 (forkhead box A1), also known as HNF3α (hepatocyte nuclear factor 3α), is required for postnatal survival due to its essential role in controlling pancreatic and renal function. In addition to regulating a variety of tissues during embryogenesis and early life, rescue experiments have revealed a specific role for FOXA1 in the postnatal development of the mammary gland and prostate. Activity of the nuclear hormone receptors ERα (oestrogen receptor α) and AR (androgen receptor) is also required for proper development of the mammary gland and prostate respectively. FOXA1 modulates ER and AR function in breast and prostate cancer cells, supporting the postulate that FOXA1 is involved in ER and AR signalling under normal conditions, and that some carcinogenic processes in these tissues stem from hormonally regulated developmental pathways gone awry. In addition to broadly reviewing the function of FOXA1 in various aspects of development and cancer, this review focuses on the interplay of FOXA1/ER and FOXA1/AR, in normal and cancerous mammary and prostate epithelial cells. Given the hormone dependency of both breast and prostate cancer, a thorough understanding of FOXA1's role in both cancer types is critical for battling hormone receptor-positive disease and acquired anti-hormone resistance.

Figure 1. FOXA1/AR signalling in prostate cancer

Lineage-specific FOXA1-binding sites are marked by histone H3, lysine 4 dimethylation (H3K4me2). Under both androgen-dependent (shown) and androgen-independent (not shown) conditions, FOXA1 mediates AR transactivation of varied responsive genes. FOXA1 and AR also directly interact. Loss of this interaction leads to AR binding and transcriptional regulation at a different set of genes (i.e. hormonal reprogramming) compared with when co-expressed with FOXA1.

Figure 2. FOXA1/ER signalling in breast cancer

(A) Lineage-specific FOXA1-binding sites are marked by histone H3, lysine 4 dimethylation (H3K4me2). FOXA1 mediates both oestrogen-induced gene transactivation and repression. (B) FOXA1 is necessary for ER expression, and expression of ER has been proposed to modulate FOXA1 expression in an oestrogen-dependent manner.