FOXA1

Summary

FOXA1 (forkhead box A1, HGNC:5021) is a protein-coding gene on chromosome 14q21.1, encoding Hepatocyte nuclear factor 3-alpha (P55317). Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues.

This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver.

Source: NCBI Gene 3169 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 87 total — 1 pathogenic
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Transcription factor: yes — 88 downstream targets (CollecTRI)
• MANE Select transcript: NM_004496

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5021
Approved symbol	FOXA1
Name	forkhead box A1
Location	14q21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000129514
Ensembl biotype	protein_coding
OMIM	602294
Entrez	3169

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 1 protein_coding, 1 nonsense_mediated_decay

ENST00000250448, ENST00000545425, ENST00000553751, ENST00000554607, ENST00000557418

RefSeq mRNA: 1 — MANE Select: NM_004496 NM_004496

CCDS: CCDS9665

Canonical transcript exons

ENST00000250448 — 2 exons

Exon	Start	End
ENSE00000995292	37589552	37592711
ENSE00001269598	37594901	37595249

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 98.02.

FANTOM5 (CAGE): breadth broad, TPM avg 28.9340 / max 746.8834, expressed in 520 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142983	23.4746	459
142984	1.7589	117
142988	1.4523	222
142982	0.7575	201
142989	0.4481	112
142985	0.4403	115
142987	0.2980	124
142986	0.1318	85
142981	0.0917	63
142991	0.0809	47

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	98.02	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.04	gold quality
epithelium of bronchus	UBERON:0002031	90.81	gold quality
bronchial epithelial cell	CL:0002328	90.76	gold quality
bronchus	UBERON:0002185	89.25	gold quality
right lobe of liver	UBERON:0001114	87.18	gold quality
prostate gland	UBERON:0002367	86.64	gold quality
rectum	UBERON:0001052	84.14	gold quality
nasal cavity epithelium	UBERON:0005384	83.79	gold quality
mucosa of transverse colon	UBERON:0004991	82.91	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.44	gold quality
nasal cavity mucosa	UBERON:0001826	81.23	gold quality
body of stomach	UBERON:0001161	80.43	gold quality
pancreatic ductal cell	CL:0002079	80.31	silver quality
minor salivary gland	UBERON:0001830	79.98	gold quality
esophagus mucosa	UBERON:0002469	79.89	gold quality
stomach	UBERON:0000945	79.74	gold quality
lower esophagus mucosa	UBERON:0035834	79.38	gold quality
liver	UBERON:0002107	77.30	gold quality
palpebral conjunctiva	UBERON:0001812	76.32	gold quality
transverse colon	UBERON:0001157	75.47	gold quality
mouth mucosa	UBERON:0003729	74.89	gold quality
urinary bladder	UBERON:0001255	74.87	gold quality
right lung	UBERON:0002167	74.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.26	gold quality
saliva-secreting gland	UBERON:0001044	74.08	gold quality
fundus of stomach	UBERON:0001160	72.79	gold quality
jejunal mucosa	UBERON:0000399	72.74	gold quality
upper lobe of left lung	UBERON:0008952	71.83	gold quality
upper lobe of lung	UBERON:0008948	70.67	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	162.09
E-ANND-3	yes	10.58

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

88 targets.

Target	Regulation
ABCA1	Repression
ADAM2
AFP	Unknown
AGR2	Unknown
ALB	Unknown
APOA1	Unknown
APOB	Activation
AR	Repression
BCL2	Repression
BMP2	Unknown
BPIFA4P	Activation
BRCA1	Unknown
CCND1	Unknown
CCNG2	Unknown
CD274	Repression
CDH17
CDKN1B	Activation
CDKN2A	Unknown
CEBPA	Unknown
CEL
CFTR	Repression
CYP3A4
CYP7A1	Unknown
DIO1	Repression
ELF3
ELK4
EN1	Unknown
ERBB3	Unknown
ESR1	Unknown
FABP1	Unknown

JASPAR motifs

Motif	Name	Family
MA0148.1	FOXA1	FOX
MA0148.2	FOXA1	FOX
MA0148.3	FOXA1	FOX
MA0148.4	FOXA1	FOX
MA0148.5	FOXA1	FOX

JASPAR matrix evidence (PMIDs): PMID:18798982

Upstream regulators (CollecTRI, top): AR, CEBPB, CEBPG, CREB1, ELF5, FOS, FOXD3, FOXJ1, GATA3, GLI1, KDM5B, KLF5, ONECUT1, POU5F1, RARA, RXRG, SNAI2, SP1, TFAP2A, TFAP2C, ZNF263

miRNA regulators (miRDB)

123 targeting FOXA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434

Literature-anchored findings (GeneRIF, showing 40)

• The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas (PMID:12234996)
• This protein up-regulates vitronectin expression during tretinoin-induced differentiation in mouse neuroblastoma Neuro2a cells. (PMID:12441652)
• the HNF-3 site in the fibrinogen beta promoter is important for IL6-induced expression, and its activity is influenced by the adjacent -148C/T polymorphism (PMID:15737987)
• The knockdown of FoxA1 expression blocks the association of ER with chromatin and estrogen-induced gene expression demonstrating the necessity of FoxA1 in mediating an estrogen response in breast cancer cells. (PMID:16009131)
• ablation of FOXA1 expression in MCF-7 cells suppressed estrogen receptor 1 binding to the prototypic TFF1 promoter (PMID:16087863)
• HNF-3alpha is an additional member of the pituitary P sequence regulatory complex, implicating it in tissue-specific expression (PMID:16239259)
• identifies high expression of FOXA1 in breast cancer cell lines and tissues; role for BRCA1 in the regulation of p27(Kip1) transcription and a possible interaction with BRCA1 discovered (PMID:16331276)
• REVIEW: The expression of FOXA1 in breast cancer, and its potential as an antineoplastic target. (PMID:17373880)
• GATA-3 as a critical component of the master cell-type-specific transcriptional network including ER alpha and FoxA1 that dictates the phenotype of hormone-dependent breast cancer (PMID:17616709)
• Loss of expression of FOXA1 expression is associated with breast cancer (PMID:17671124)
• Our present results suggest that FoxA1 plays an important role as a lineage-specific oncogene in proliferation of cancer cells derived from mammary luminal cells. (PMID:18039470)
• Taken together, our findings indicate that HNF-3alpha is a novel corepressor of AR, and predict its effects on the proliferation of prostate cancer cells. (PMID:18178153)
• The results suggest that methylation of histone H3 lysine 4 is part of the epigenetic signature that defines lineage-specific FoxA1 recruitment sites in chromatin. (PMID:18358809)
• FOXA1 protein is associated with markers of good prognosis supporting its role as a growth repressor in breast cancer. (PMID:18538561)
• FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation (PMID:18688264)
• Foxa1 protein decreased the transcription activity of Proto-Oncogene Proteins c-bcl-2 promoter under normal conditions and oxidative stress. (PMID:19127412)
• Mechanisms that restrict the activity of shared FOXA1-bound enhancers likely play a significant role in defining the cell-type-specific functions of FOXA1. (PMID:19129543)
• REVIEW: The transcription factor network composed of the estrogen receptor alpha, FOXA1 and GATA3 may control the gene expression pattern in luminal subtype A breast cancers (PMID:19261198)
• These data suggest a mechanistic link between rs1230399 and bone mineral density through estrogen ERalpha/FOXA1 signaling pathways driven by long-distance enhancers. (PMID:19371798)
• These results show that FOXA plays a role in the transcriptional regulation of CIC and in insulin secretion. (PMID:19445897)
• Data show that FOXA1 may be an important oncogene in thyroid tumorigenesis and a potential new therapeutic target for the treatment of anaplastic thyroid cancers. (PMID:19470727)
• These results indicate an important role for Foxa1 as a novel regulator of expression of HSP72. (PMID:19486887)
• FOXA1 and GATA-3 have roles in breast cancer, but FOXA1 is expressed in patients with good outcome, while GATA-3 is a luminal marker (PMID:19549328)
• Data show a direct physical interaction between FoxA1 and USF2. This interaction is mediated via the forkhead DNA-binding domain of FoxA1 and the DNA-binding domain of USF2 (PMID:19846536)
• The results of the current study suggest a novel function of HNF-3alpha as a killer of malignant prostate cancer cells. (PMID:19866472)
• Stable chromatin binding protects the FoxA DNA-binding domain from acetylation to preserve chromatin binding and remodeling by FoxA factors in the absence of extracellular cues. (PMID:19897491)
• these data implicate a novel role for HDAC7 and FoxA1 in estrogen repression of RPRM. (PMID:19917725)
• analysis of the binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells (PMID:19919681)
• Data demonstrate that FOXA1 directly regulates HOXB13 in human prostate epithelial cells, and show that this prostate-specific regulatory mechanism is conserved in mice. (PMID:20018680)
• FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic esophageal squamous cell carcinomas with metastatic lymph nodes (PMID:20043065)
• our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer. (PMID:20048076)
• Data show that genes overexpressed in breast carcinoma including TFF1, TFF3, FOXA1 and CA12. (PMID:20132413)
• In pancreatic cancer cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. (PMID:20160041)
• FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis. (PMID:20501593)
• Expression levels of Wnt7A, beta-catenin, and FoxA1, along with cell-type specific markers, are observed to vary with differentiation and often also in response to the presence of heparin during the time of exposure to heparin. (PMID:20503388)
• CCCTC-binding factor acts upstream of FOXA1 and demarcates the genomic response to estrogen. (PMID:20610384)
• A novel polymorphism in FOXA1 is identified as an important regulator of UDP glucuronosyltransferase 2B17 (UGT2B17) expression in prostate cancer. (PMID:20628005)
• The expression of FOXA1 is associated with a good prognosis in invasive ductal breast carcinoma. (PMID:20646630)
• regulation of the UGT2B15 and UGT2B17 genes by FOXA1 may have an important role in the maintenance of androgen homeostasis within prostate cancer cells. (PMID:20736324)
• These results show that FOXA and Sp1 sites in HepG2 cells and only the Sp1 site in HEK293 and SK-N-SH cells have a critical role in the transcriptional regulation of the CAC proximal promoter. (PMID:21130740)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxa1	ENSDARG00000102138
mus_musculus	Foxa1	ENSMUSG00000035451
rattus_norvegicus	Foxa1	ENSRNOG00000009284

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Hepatocyte nuclear factor 3-alpha — P55317 (reviewed: P55317)

Alternative names: Forkhead box protein A1, Transcription factor 3A

All UniProt accessions (2): P55317, G3V4B9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a ‘pioneer’ factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5’-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3’. Proposed to play a role in translating the epigenetic signatures into cell type-specific enhancer-driven transcriptional programs. Its differential recruitment to chromatin is dependent on distribution of histone H3 methylated at ‘Lys-5’ (H3K4me2) in estrogen-regulated genes. Involved in the development of multiple endoderm-derived organ systems such as liver, pancreas, lung and prostate; FOXA1 and FOXA2 seem to have at least in part redundant roles. Modulates the transcriptional activity of nuclear hormone receptors. Is involved in ESR1-mediated transcription; required for ESR1 binding to the NKX2-1 promoter in breast cancer cells; binds to the RPRM promoter and is required for the estrogen-induced repression of RPRM. Involved in regulation of apoptosis by inhibiting the expression of BCL2. Involved in cell cycle regulation by activating expression of CDKN1B, alone or in conjunction with BRCA1. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis.

Subunit / interactions. Binds DNA as a monomer. Interacts with FOXA2. Interacts with NKX2-1. Interacts with HDAC7. Interacts with the histone H3-H4 heterodimer. Associates with nucleosomes containing histone H2A. Interacts with AR. Interacts with NR0B2.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in prostate and ESR1-positive breast tumors. Overexpressed in esophageal and lung adenocarcinomas.

Isoforms (2)

UniProt ID	Names	Canonical?
P55317-1	1	yes
P55317-2	2

RefSeq proteins (1): NP_004487* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR013638	Fork-head_N	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR018533	Forkhead_box_C	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050211	FOX_domain-containing	Family

Pfam: PF00250, PF08430, PF09354

UniProt features (24 total): sequence variant 6, helix 5, strand 3, compositionally biased region 3, modified residue 2, chain 1, DNA-binding region 1, region of interest 1, turn 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7VOX	X-RAY DIFFRACTION	2.1
8VG1	ELECTRON MICROSCOPY	2.48
8VFY	ELECTRON MICROSCOPY	2.89
8VG2	ELECTRON MICROSCOPY	3.04
8VFZ	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55317-F1	57.42	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 307, 331

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9796292	Formation of axial mesoderm

MSigDB gene sets: 350 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, FXR_IR1_Q6, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GU_PDEF_TARGETS_DN, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_PROSTATE_GLAND_MORPHOGENESIS, PID_HNF3B_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_EPITHELIAL_CELL_DEVELOPMENT, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS

GO Biological Process (43): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin remodeling (GO:0006338), regulation of transcription by RNA polymerase II (GO:0006357), Notch signaling pathway (GO:0007219), smoothened signaling pathway (GO:0007224), anatomical structure morphogenesis (GO:0009653), negative regulation of epithelial to mesenchymal transition (GO:0010719), dorsal/ventral neural tube patterning (GO:0021904), cell differentiation (GO:0030154), response to estradiol (GO:0032355), positive regulation of intracellular estrogen receptor signaling pathway (GO:0033148), hormone metabolic process (GO:0042445), glucose homeostasis (GO:0042593), positive regulation of apoptotic process (GO:0043065), positive regulation of smoothened signaling pathway (GO:0045880), positive regulation of mitotic cell cycle (GO:0045931), positive regulation of transcription by RNA polymerase II (GO:0045944), anatomical structure formation involved in morphogenesis (GO:0048646), neuron fate specification (GO:0048665), obsolete positive regulation of DNA-binding transcription factor activity (GO:0051091), epithelial tube branching involved in lung morphogenesis (GO:0060441), lung epithelial cell differentiation (GO:0060487), secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development (GO:0060528), mesenchymal-epithelial cell signaling involved in prostate gland development (GO:0060739), prostate gland epithelium morphogenesis (GO:0060740), prostate gland stromal morphogenesis (GO:0060741), epithelial cell maturation involved in prostate gland development (GO:0060743), alveolar secondary septum development (GO:0061144), dopaminergic neuron differentiation (GO:0071542), respiratory basal cell differentiation (GO:1902691), positive regulation of miRNA transcription (GO:1902895), positive regulation of dopaminergic neuron differentiation (GO:1904340), positive regulation of cell-cell adhesion mediated by cadherin (GO:2000049), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), neuron differentiation (GO:0030182), lung development (GO:0030324), prostate gland development (GO:0030850), tube morphogenesis (GO:0035239)

GO Molecular Function (12): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), protein domain specific binding (GO:0019904), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), transcription factor binding (GO:0008134), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (5): chromatin (GO:0000785), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), microvillus (GO:0005902)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
ESR-mediated signaling	1
Gastrulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
cell surface receptor signaling pathway	2
developmental process	2
binding	2
protein binding	2
negative regulation of DNA-templated transcription	1
chromatin organization	1
anatomical structure development	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
dorsal/ventral pattern formation	1
neural tube patterning	1
cellular developmental process	1
response to lipid	1
response to oxygen-containing compound	1
estrogen receptor signaling pathway	1
positive regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of intracellular estrogen receptor signaling pathway	1
metabolic process	1
regulation of hormone levels	1
carbohydrate homeostasis	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
positive regulation of cell cycle	1
positive regulation of DNA-templated transcription	1
anatomical structure morphogenesis	1
cell fate specification	1
neuron fate commitment	1

Protein interactions and networks

STRING

3720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXA1	ESR1	P03372	990
FOXA1	AR	P10275	987
FOXA1	HDAC7	Q8WUI4	954
FOXA1	GATA3	P23771	950
FOXA1	HDAC9	Q9UKV0	881
FOXA1	GATA6	P78327	866
FOXA1	PBX1	P40424	855
FOXA1	TLE3	Q04726	850
FOXA1	HNF1A	P20823	847
FOXA1	ONECUT1	Q9UBC0	846
FOXA1	HNF4A	P41235	822
FOXA1	GATA4	P43694	807
FOXA1	CEBPA	P49715	801
FOXA1	POU5F1	P31359	792
FOXA1	SOX17	Q9H6I2	783

IntAct

45 interactions, top by confidence:

A	B	Type	Score
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
AR	FOXA1	psi-mi:“MI:0915”(physical association)	0.710
AR	KMT2D	psi-mi:“MI:0914”(association)	0.600
FOXA1	RARA	psi-mi:“MI:0914”(association)	0.530
RARA	FOS	psi-mi:“MI:0914”(association)	0.460
FOXA1	NKX2-1	psi-mi:“MI:0915”(physical association)	0.400
FOXA1	SMAD3	psi-mi:“MI:0915”(physical association)	0.400
FOXA1	TLE1	psi-mi:“MI:0915”(physical association)	0.370
SEZ6L2	FOXA1	psi-mi:“MI:0915”(physical association)	0.370
RARA	POLR1A	psi-mi:“MI:0914”(association)	0.350
ESR1	FOS	psi-mi:“MI:0914”(association)	0.350
FOXA1	GATA3	psi-mi:“MI:0914”(association)	0.350
FOXA1	FOXC1	psi-mi:“MI:0914”(association)	0.350
FOXA1		psi-mi:“MI:0914”(association)	0.350
FOXA1	NFIC	psi-mi:“MI:0914”(association)	0.350
FOXA1	PLOD2	psi-mi:“MI:0914”(association)	0.350
PLOD1	COL25A1	psi-mi:“MI:0914”(association)	0.350
FOXA1	AREG	psi-mi:“MI:0914”(association)	0.350
	FOXA1	psi-mi:“MI:0914”(association)	0.350
PLOD1	PLK4	psi-mi:“MI:0914”(association)	0.350
FOXA1	TBP	psi-mi:“MI:0403”(colocalization)	0.350
AR	MED6	psi-mi:“MI:2364”(proximity)	0.270
RAVER1	KDM6A	psi-mi:“MI:2364”(proximity)	0.270
NFIA	BCL9	psi-mi:“MI:2364”(proximity)	0.270
NFIB	BCL9	psi-mi:“MI:2364”(proximity)	0.270
AKT1	FOXA1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (581): FOXA1 (Affinity Capture-MS), PIAS1 (Affinity Capture-Western), AR (Affinity Capture-Western), PIAS1 (Co-localization), SATB1 (Affinity Capture-MS), SATB2 (Affinity Capture-MS), NAA40 (Affinity Capture-MS), RECQL (Affinity Capture-MS), CREB1 (Affinity Capture-MS), HOXB9 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NFIX (Affinity Capture-MS), DLX1 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), HOXD13 (Affinity Capture-MS)

ESM2 similar proteins: A1YFU7, A2AJK6, A2BH40, B2RWS6, D3YWE6, E9Q4N7, M9NEY8, O00512, O14497, O35126, O42368, O43365, O57401, P02831, P02833, P22810, P23441, P23512, P25822, P32182, P34545, P35582, P35583, P43698, P43699, P50220, P50901, P54258, P54259, P54269, P55317, Q06A37, Q08DG7, Q08E31, Q09472, Q0VCT9, Q10571, Q1KKX7, Q24248, Q24645

Diamond homologs: A0A2Z4LIS9, A3RK74, A3RK75, A4L7N3, A8MYZ6, B3LYS5, B3P0K6, B4G4S8, B4HF64, B4JSC2, B4KBF6, B4MB78, B4NFR1, B4PTD3, E1BPQ1, G3V7R4, O16850, O43524, P0CG31, P23512, P32182, P32183, P32315, P33205, P33206, P35582, P35583, P35584, P55317, P55318, P84961, P98177, Q07342, Q10924, Q12778, Q28EM1, Q298W7, Q3Y598, Q4VUF1, Q63248

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
FOXA1	“up-regulates quantity by expression”	CDKN1B	“transcriptional regulation”
FOXA1	“down-regulates quantity by repression”	BCL2	“transcriptional regulation”
FOXA1	up-regulates	Apoptosis
FOXA1	up-regulates	NFIB	binding
FOXA1	up-regulates	NFIX	binding
FOXA1	“down-regulates quantity by repression”	AR	“transcriptional regulation”
FOXA1	“up-regulates quantity by expression”	HSPA1A	“transcriptional regulation”
FOXA1	“up-regulates quantity by expression”	HSPA1B	“transcriptional regulation”
FOXA1	“up-regulates quantity by expression”	LOXL2	“transcriptional regulation”
FOXA1	“up-regulates quantity by expression”	KRT7	“transcriptional regulation”
SMAD3	“down-regulates activity”	FOXA1	binding
FOXA1	“up-regulates quantity by expression”	SFTPB	“transcriptional regulation”
FOXA1	up-regulates	Cell_death

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	5	75.7×	2e-06
Extra-nuclear estrogen signaling	5	29.4×	5e-05
ESR-mediated signaling	5	22.1×	1e-04
Signaling by Nuclear Receptors	5	17.6×	2e-04
Epigenetic regulation of gene expression	7	17.2×	2e-05
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	16.7×	2e-04
Diseases of signal transduction by growth factor receptors and second messengers	6	11.8×	2e-04
PIP3 activates AKT signaling	5	11.5×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
glial cell proliferation	5	143.1×	4e-08
negative regulation of miRNA transcription	5	100.7×	2e-07
positive regulation of miRNA transcription	8	75.0×	3e-11
cell population proliferation	5	16.6×	3e-04
transcription by RNA polymerase II	7	15.9×	2e-05
in utero embryonic development	6	13.9×	2e-04
gene expression	5	12.9×	8e-04
positive regulation of gene expression	8	10.0×	7e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — BRCA, PRAD.

Clinical variants and AI predictions

ClinVar

87 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	76
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
57776	GRCh38/hg38 14q13.3-21.1(chr14:37121338-37866986)x1	Pathogenic

SpliceAI

400 predictions. Top by Δscore:

Variant	Effect	Δscore
14:37594898:CA:C	donor_loss	1.0000
14:37594899:ACCT:A	donor_gain	1.0000
14:37594900:C:A	donor_loss	1.0000
14:37594900:CCTC:C	donor_gain	1.0000
14:37594902:T:TA	donor_gain	1.0000
14:37594900:CCT:C	donor_gain	0.9900
14:37594892:G:A	donor_gain	0.9800
14:37594899:A:AC	donor_gain	0.9800
14:37594900:C:CC	donor_gain	0.9800
14:37592710:GCC:G	acceptor_loss	0.9200
14:37592711:CCTGG:C	acceptor_loss	0.9200
14:37592712:CTGGA:C	acceptor_loss	0.9200
14:37592713:T:C	acceptor_loss	0.9200
14:37592725:A:T	acceptor_gain	0.9200
14:37594453:A:C	donor_gain	0.9200
14:37594887:G:A	donor_gain	0.9000
14:37594903:C:A	donor_gain	0.9000
14:37594922:G:C	donor_gain	0.9000
14:37594899:ACC:A	donor_gain	0.8800
14:37594070:TTTTA:T	donor_loss	0.8700
14:37594071:TTTAC:T	donor_loss	0.8700
14:37594072:TTA:T	donor_loss	0.8700
14:37594073:TACCT:T	donor_loss	0.8700
14:37594075:CCT:C	donor_loss	0.8700
14:37594277:TGCC:T	donor_gain	0.8600
14:37592712:C:CC	acceptor_gain	0.8500
14:37594076:C:G	donor_loss	0.8500
14:37594897:TCACC:T	donor_gain	0.8500
14:37592707:TAGGC:T	acceptor_gain	0.8200
14:37594027:A:AC	donor_gain	0.8200

AlphaMissense

3094 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:37591570:A:G	L405P	1.000
14:37591579:A:G	I402T	1.000
14:37591579:A:T	I402N	1.000
14:37591584:G:C	F400L	1.000
14:37591584:G:T	F400L	1.000
14:37591585:A:C	F400C	1.000
14:37591585:A:G	F400S	1.000
14:37591586:A:G	F400L	1.000
14:37591986:G:C	F266L	1.000
14:37591986:G:T	F266L	1.000
14:37591987:A:C	F266C	1.000
14:37591987:A:G	F266S	1.000
14:37591988:A:C	F266V	1.000
14:37591988:A:G	F266L	1.000
14:37591988:A:T	F266I	1.000
14:37591991:G:A	R265C	1.000
14:37591991:G:T	R265S	1.000
14:37591992:C:A	K264N	1.000
14:37591992:C:G	K264N	1.000
14:37591993:T:A	K264M	1.000
14:37591994:T:C	K264E	1.000
14:37591995:C:A	Q263H	1.000
14:37591995:C:G	Q263H	1.000
14:37591999:C:A	R262L	1.000
14:37591999:C:G	R262P	1.000
14:37591999:C:T	R262H	1.000
14:37592000:G:A	R262C	1.000
14:37592000:G:C	R262G	1.000
14:37592000:G:T	R262S	1.000
14:37592002:C:T	R261H	1.000

dbSNP variants (sampled 300 via entrez): RS1000211851 (14:37595824 A>C,G), RS1000306350 (14:37589181 C>G), RS1000358414 (14:37589650 GTAGT>G), RS1000412963 (14:37594280 C>T), RS1000603594 (14:37595572 A>G), RS1000751022 (14:37592888 G>T), RS1001304639 (14:37591169 A>G), RS1001693050 (14:37595554 C>A,T), RS1002060243 (14:37594613 G>A,C), RS1002658235 (14:37596463 G>A), RS1002749626 (14:37589897 A>G,T), RS1003100948 (14:37596790 T>C), RS1003535488 (14:37590351 C>A,T), RS1003698404 (14:37592866 C>T), RS1004333665 (14:37595230 G>A)

Disease associations

OMIM: gene MIM:602294 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002083_9	Self-reported allergy	5.000000e-08
GCST002126_6	Periodontitis (CDC/AAP)	7.000000e-06
GCST002929_15	Chromium levels	6.000000e-07
GCST003192_2	Coronary artery aneurysm in Kawasaki disease	9.000000e-06
GCST003805_7	Diastolic blood pressure response to hydrochlorothiazide in hypertension	6.000000e-06
GCST003990_17	Allergy	4.000000e-10
GCST003995_9	Tonsillectomy	8.000000e-13
GCST005014_96	Tonsillectomy	8.000000e-13
GCST005038_85	Allergic disease (asthma, hay fever or eczema)	8.000000e-09
GCST005580_81	Intraocular pressure	2.000000e-11
GCST005580_88	Intraocular pressure	4.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006945	diastolic blood pressure change measurement
EFO:0007924	tonsillectomy risk measurement
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

84 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects reaction, affects binding, decreases reaction, affects cotreatment, decreases expression (+2 more)	5
Tretinoin	affects cotreatment, decreases reaction, increases expression, affects expression	4
Benzo(a)pyrene	increases expression, decreases expression	3
Tetrachlorodibenzodioxin	increases expression, affects response to substance, affects binding, affects reaction, decreases expression (+2 more)	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
methylselenic acid	decreases expression	2
arsenite	affects binding, decreases reaction, decreases expression	2
sodium arsenite	decreases reaction, increases expression	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression, decreases reaction, affects cotreatment, increases reaction	2
Bortezomib	affects cotreatment, increases expression, decreases expression	2
Resveratrol	increases activity, increases reaction, increases expression, increases phosphorylation	2
Arsenic Trioxide	affects methylation, affects cotreatment, increases expression	2
Cadmium	increases abundance, increases expression, decreases expression	2
Carbamazepine	affects expression	2
Choline	affects cotreatment, decreases expression, increases reaction, affects expression, decreases reaction	2
Quercetin	affects cotreatment, decreases expression, decreases reaction	2
Tamoxifen	affects activity, affects reaction, decreases expression	2
Valproic Acid	increases expression, increases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
4-oxoretinoic acid	increases expression	1
bisphenol A	decreases expression, decreases reaction, affects reaction, increases expression	1
sodium arsenate	increases abundance, increases expression	1
terbufos	increases methylation	1
trichostatin A	affects cotreatment, decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1W2	SEES3-1V human FOXA1, clone1	Embryonic stem cell	Male
CVCL_A1W3	SEES3-1V human FOXA1, clone2	Embryonic stem cell	Male
CVCL_A1W4	SEES3-1V human FOXA1, clone3	Embryonic stem cell	Male
CVCL_B1SB	Abcam HeLa FOXA1 KO	Cancer cell line	Female
CVCL_B8GB	Abcam HCT 116 FOXA1 KO	Cancer cell line	Male
CVCL_B9IK	Abcam A-549 FOXA1 KO	Cancer cell line	Male
CVCL_D6A1	HyCyte 22Rv1 KO-hFOXA1	Cancer cell line	Male
CVCL_E1LT	HyCyte LNCaP KO-hFOXA1	Cancer cell line	Male
CVCL_XN89	HAP1 FOXA1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

11 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery