FOXA1


Forkhead box protein A1, also known as hepatocyte nuclear factor 3-alpha, is a protein that in humans is encoded by the FOXA1 gene.

Structure

FOXA1 is a member of the forkhead domain transcription factor family. The forkhead domain is essential for its DNA-binding function, and consists of three alpha helices, three beta strands, and two loops. The domain binds along the DNA major groove and the wings directly contact the DNA.
FOXA1 is modified by the O-GlcNAc post-translational modification.

Function

FOXA1 is a pioneer factor, a transcription factor that directly binds condensed chromatin, facilitating the binding of other transcription factors. In prostate cells, FOXA1 interacts with the androgen receptor to drive transcription of prostate-specific genes.
FOXA1 is a member of the forkhead class of DNA-binding proteins. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver.

Clinical significance

Role in cancer

FOXA1 is one of the most frequently altered genes in prostate cancer, with mutations in the coding sequence of up to 9% of localized prostate cancer cases, and 13% of metastatic treatment-resistant prostate cancers. Most cancer-associated FOXA1 mutations are missense mutations, changing the amino acid sequence of the fork head domain's DNA-binding sites.
Expression of FOXA1 correlates with two EMT markers, namely Twist1 and E-cadherin in breast cancer.
FOXA1 is mutated in approximately 10% of primary prostate cancer, and this percentage increases in metastatic castration-resistant prostate cancer. A 2025 study found that distinct mutational classes of FOXA1 diverge to drive tumor progression or therapy-resistant cellular plasticity, with Class 1 mutations promoting androgen-dependent adenocarcinomas through coactivation of mTORC1/2 and oncogenic AR signaling.

Marker in breast cancer

FOXA1 in breast cancer is highly correlated with ERα+, GATA3+, and PR+ protein expression as well as endocrine signaling. FOXA1 acts as a pioneer factor for ERa in ERα+ breast cancer, and its expression might identify ERα+ cancers that undergo rapid reprogramming of ERa signaling that is associated with poor outcomes and treatment resistance. Conversely, in ERα− breast cancer FOXA1 is highly correlated with low-grade morphology and improved disease free survival. FOXA1 is a downstream target of GATA3 in the mammary gland. Expression in ERα− cancers may identify a subset of tumors that is responsive to other endocrine therapies such as androgen receptor antagonist treatment.

Chemical probe development

Being a transcription factor lacking structurally ordered small molecule-binding sites, FOXA1 has generally been considered to be an undruggable protein. Using a chemical proteomics approach directed against cysteines, researchers from Scripps Research identified a tryptoline acrylamide chemical probe WX-02-23 that reacts with FOXA1 C258 site-specifically and stereospecifically. WX-02-23 binds FOXA1 in a DNA-dependent manner, and WX-02-23 likewise enhances FOXA1 interaction with DNA.