Forkhead box protein A1 (FOXA1), also known ashepatocyte nuclear factor 3-alpha (HNF-3A), is aprotein that in humans is encoded by theFOXA1gene.[5][6][7]
FOXA1 is a member of the forkhead domain transcription factor family. The forkhead domain is essential for its DNA-binding function, and consists of threealpha helices, threebeta strands, and two loops (called "wings"). The domain binds along the DNAmajor groove and the wings directly contact the DNA.[8]
FOXA1 is a member of theforkhead 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.[5]
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.[10] Most cancer-associated FOXA1 mutations aremissense mutations, changing theamino acid sequence of thefork head domain's DNA-binding sites.[10]
Expression of FOXA1 correlates with twoEMT markers, namelyTwist1 andE-cadherin in breast cancer.[11]
FOXA1 is mutated in approximately 10% of primary prostate cancer (PCa), and this percentage increases in metastatic castration-resistant prostate cancer (CRPC). 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.[12]
FOXA1 inbreast cancer is highly correlated withERα+,GATA3+, andPR+protein expression as well asendocrine signaling. FOXA1 acts as apioneer 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.[13] Conversely, in ERα− breast cancer FOXA1 is highly correlated with low-grade morphology and improved disease free survival. FOXA1 is a downstream target ofGATA3 in the mammary gland.[14] Expression in ERα− cancers may identify a subset of tumors that is responsive to other endocrine therapies such asandrogen receptor antagonist treatment.[15][16]
Being a transcription factor lacking structurally ordered small molecule-binding sites, FOXA1 has generally been considered to be anundruggable protein. Using a chemical proteomics approach directed againstcysteines, researchers fromScripps 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.[17]
^Bingle CD, Gowan S (June 1996). "Molecular cloning of the forkhead transcription factor HNF-3 alpha from a human pulmonary adenocarcinoma cell line".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.1307 (1):17–20.doi:10.1016/0167-4781(96)00058-9.PMID8652662.
^Mincheva A, Lichter P, Schütz G, Kaestner KH (February 1997). "Assignment of the human genes for hepatocyte nuclear factor 3-alpha, -beta, and -gamma (HNF3A, HNF3B, HNF3G) to 14q12-q13, 20p11, and 19q13.2-q13.4".Genomics.39 (3):417–419.doi:10.1006/geno.1996.4477.PMID9119385.
^BenAyed-Guerfali D, Dabbèche-Bouricha E, Ayadi W, Trifa F, Charfi S, Khabir A, et al. (June 2019). "Association of FOXA1 and EMT markers (Twist1 and E-cadherin) in breast cancer".Molecular Biology Reports.46 (3):3247–3255.doi:10.1007/s11033-019-04784-w.PMID30941644.S2CID91190545.
