Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

FOXA1 (forkhead box A1)

Written2010-07Harikrishna Nakshatri, Sunil Badve
Department of Surgery, Biochemistry, Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA (HN); Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA (SB)

(Note : for Links provided by Atlas : click)

Identity

Other aliasHNF3A
MGC33105
TCF3A
LocusID (NCBI) 3169
Atlas_Id 44403
Location 14q21.1  [Link to chromosome band 14q21]
Location_base_pair Starts at and ends at bp from pter
 
  FOXA1 is located on chromosome 14q21.1 and the transcribed region including an intron spans only 5300 bases. This protein binds to chromatinized DNA and, therefore, described as a "pioneer factor".
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ERBB3 (12q13.2) / FOXA1 (14q21.1)OSBPL3 (7p15.3) / FOXA1 (14q21.1)

DNA/RNA

 
Description The transcribed region of FOXA1 extends only to 5400 bases and contains two exons and one intron. This gene is amplified in breast, esophageal, lung, and thyroid carcinomas. No deletions or chromosomal translocations have been reported. MIPOL1 and C14orf25 are the two adjoining genes. MIPOL1 has been described as a tumor suppressor gene in nasopharyngeal carcinoma, whereas the function of C14orf25 is unknown.
Transcription FOXA1 is expressed predominantly in liver and is highly responsive to hormonal manipulation. Insulin suppresses its expression in embryonic stem cells as well as in breast cancer cells, whereas retinoic acid, estrogen, androgen, and heregulin induce its expression. The developmental transcription factors Oct-4 and SOX4 repress FOXA1 expression, whereas SOX17 and GATA-3 increase its expression. No splice variants have been reported. 542 base long promoter/enhancer is sufficient for liver-specific expression. This region binds to transcription factors TTF1 and NF-1. By binding to its own enhancer/promoter, FOXA1 autoregulates its expression. Peroxisome Proliferator Activated Receptor gamma also upregulates FOXA1 expression, although region of the promoter/enhancer involved in this upregulation is yet to be characterized.

Protein

 
Description FOXA1 is a 473 amino acid long transcription factor that binds to the consensus sequence A(A/T)TRTT(G/T)RYTY using the central region of the protein. Crystallography showed DNA binding domain in a winged helix-loop-helix configuration. Both N-terminus and C-terminus have transactivation domains. In silico analysis revealed 11 putative acetylation sites; acetylation sites in the DNA binding domain inhibit interaction with chromatin. The N-terminus has a putative caseine kinase 1 phosphorylation site.
Expression FOXA1 was originally identified as a transcription factor that regulates gene expression in endoderm-derived tissues such as liver and lungs. Subsequent studies showed expression in pancreas, breast, prostate, bladder, intestine, and seminal vesicle. During embryogenesis, expression is seen in tissues derived from both foregut and hindgut endoderm (liver, lung, pancreas, stomach, intestine, prostate, and bladder). Organs derived from ectoderm (forebrain, floor plate, olfactory epithelium) and mesoderm (kidney, vagina, uterus, seminal and coagulating glands) also show expression. FOXA1 along with FOXA2 is required for normal bile duct development as deletion of FOXA1/2 in embryonic liver leads to hyperplasia of the billiary tree. Absence of FOXA1 in mammary gland leads to impaired ductal morphogenesis and reduction in the number of estrogen receptor-positive luminal epithelial cells.
Localisation FOXA1 is localized predominantly in the nucleus. transforming growth factor beta 1 treatment results in cytoplasmic localization of the protein, which may be dependent on protein kinase C.
Function FOXA1 binds to chromatinized DNA and opens the chromatin to allow binding of additional transcription factors. Specific histone modification such as histone H3 lysine 4 methylation guides recruitment of other factors. FOXA1 facilitates the recruitment of nuclear receptors including estrogen receptor, androgen receptor and glucocorticoid receptor. FOXA1 binding leads to both activation or repression of genes. These gene-specific effects involve interaction with or recruitment of other transcription factors such as SRC-3, USF2, TLE3, COUP-TFII, SHP, SMAD3, and HDAC7.
Homology FOXA1 belongs to the 40-member FOX family of transcription factors. FOXA1, FOXA2, and FOXA3 form a subfamily and share a 110 amino acid long DNA binding domain with only 7 amino acid difference.

Mutations

Germinal Coding region variation Ala83Thr, which is within the N-terminal transactivation domain, has been observed. However, this variation is not linked to breast cancer or maturity onset diabetes.

Implicated in

Note
  
Entity Breast cancer
Disease Breast cancers that express estrogen receptor and progestrone receptor (ER+/PR+) demonstrate elevated FOXA1 expression. Amplification of the genomic region encompassing FOXA1 is also observed in ER+/PR+ breast cancer. A small subgroup of ER-/PR- negative breast cancers express FOXA1 and ER-/FOXA1- tumors show 3.6 fold enhanced recurrence rate compared to ER-/FOXA1+ tumors.
Prognosis FOXA1-positivity ER+/PR+ breast cancer is associated with favorable prognosis.
  
  
Entity Prostate cancer
Disease FOXA1 is expressed in prostate cancer regardless of Gleason grade score and the expression is higher in metastatic disease. In transgenic animal models of prostate cancer, FOXA1 expression is seen in neuroendocrine carcinomas.
  
  
Entity Pancreatic cancer
Disease FOXA1 is expressed in normal and well-differentiated cancer but the expression is lost in undifferentiated cancer cells. Loss of FOXA1 expression correlates with epithelial-to-mesenchymal transition.
  
  
Entity Esophageal squamous cell carcinoma
Disease Cancers that have metastasized to lymphnodes express higher levels of FOXA1 along with its target gene KRT7.
  
  
Entity Anaplastic thyroid carcinoma
Disease Overexpressed in aggressive thyroid cancers and is amplified in these cancers. FOXA1 increases proliferation of these cells.
  
  
Entity Diabetes
Disease FOXA1 deficient mice are growth retarded and hypoglycemic due to defects in insulin secretion. However, the corresponding effects in human have not been reported.
  
  
Entity Diet restriction-induced longevity
Note PHA-4, the FOXA1, A2 and A3 ortholog in C. elegans is essential for diet-restriction-induced longevity.
  

Bibliography

Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours.
Albergaria A, Paredes J, Sousa B, Milanezi F, Carneiro V, Bastos J, Costa S, Vieira D, Lopes N, Lam EW, Lunet N, Schmitt F.
Breast Cancer Res. 2009;11(3):R40. Epub 2009 Jun 23.
PMID 19549328
 
FOXA1 expression in breast cancer--correlation with luminal subtype A and survival.
Badve S, Turbin D, Thorat MA, Morimiya A, Nielsen TO, Perou CM, Dunn S, Huntsman DG, Nakshatri H.
Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4415-21.
PMID 17671124
 
FoxA1 binding directs chromatin structure and the functional response of a glucocorticoid receptor-regulated promoter.
Belikov S, Astrand C, Wrange O.
Mol Cell Biol. 2009 Oct;29(20):5413-25. Epub 2009 Aug 17.
PMID 19687299
 
FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis.
Bernardo GM, Lozada KL, Miedler JD, Harburg G, Hewitt SC, Mosley JD, Godwin AK, Korach KS, Visvader JE, Kaestner KH, Abdul-Karim FW, Montano MM, Keri RA.
Development. 2010 Jun;137(12):2045-54.
PMID 20501593
 
Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues.
Besnard V, Wert SE, Hull WM, Whitsett JA.
Gene Expr Patterns. 2004 Dec;5(2):193-208.
PMID 15567715
 
Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1.
Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR, Fox EA, Silver PA, Brown M.
Cell. 2005 Jul 15;122(1):33-43.
PMID 16009131
 
Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer.
Chiaverotti T, Couto SS, Donjacour A, Mao JH, Nagase H, Cardiff RD, Cunha GR, Balmain A.
Am J Pathol. 2008 Jan;172(1):236-46. Epub 2007 Dec 21.
PMID 18156212
 
Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4.
Cirillo LA, Lin FR, Cuesta I, Friedman D, Jarnik M, Zaret KS.
Mol Cell. 2002 Feb;9(2):279-89.
PMID 11864602
 
Regulation of a transcription factor network required for differentiation and metabolism.
Duncan SA, Navas MA, Dufort D, Rossant J, Stoffel M.
Science. 1998 Jul 31;281(5377):692-5.
PMID 9685261
 
The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression.
Guo Y, Costa R, Ramsey H, Starnes T, Vance G, Robertson K, Kelley M, Reinbold R, Scholer H, Hromas R.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3663-7. Epub 2002 Mar 12.
PMID 11891324
 
Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort.
Haiman CA, Garcia RR, Hsu C, Xia L, Ha H, Sheng X, Le Marchand L, Kolonel LN, Henderson BE, Stallcup MR, Greene GL, Press MF.
BMC Cancer. 2009 Jan 30;9:43.
PMID 19183483
 
The evolution of Fox genes and their role in development and disease.
Hannenhalli S, Kaestner KH.
Nat Rev Genet. 2009 Apr;10(4):233-40. (REVIEW)
PMID 19274050
 
Genetic alterations and oncogenic pathways associated with breast cancer subtypes.
Hu X, Stern HM, Ge L, O'Brien C, Haydu L, Honchell CD, Haverty PM, Peters BA, Wu TD, Amler LC, Chant J, Stokoe D, Lackner MR, Cavet G.
Mol Cancer Res. 2009 Apr;7(4):511-22.
PMID 19372580
 
Expression of high Forkhead box protein A1 in metastatic prostate cancer.
Jain RK, Mehta R, Nakshatri H, Idress M, Badve S.
Histopathology 2010 (in press).
 
Stable chromatin binding prevents FoxA acetylation, preserving FoxA chromatin remodeling.
Kohler S, Cirillo LA.
J Biol Chem. 2010 Jan 1;285(1):464-72. Epub 2009 Nov 5.
PMID 19897491
 
Transforming growth factor-beta(1) regulation of surfactant protein B gene expression is mediated by protein kinase-dependent intracellular translocation of thyroid transcription factor-1 and hepatocyte nuclear factor 3.
Kumar AS, Gonzales LW, Ballard PL.
Biochim Biophys Acta. 2000 Jun 21;1492(1):45-55.
PMID 11004479
 
Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head.
Lai E, Prezioso VR, Tao WF, Chen WS, Darnell JE Jr.
Genes Dev. 1991 Mar;5(3):416-27.
PMID 1672118
 
Global characterization of transcriptional impact of the SRC-3 coregulator.
Lanz RB, Bulynko Y, Malovannaya A, Labhart P, Wang L, Li W, Qin J, Harper M, O'Malley BW.
Mol Endocrinol. 2010 Apr;24(4):859-72. Epub 2010 Feb 24.
PMID 20181721
 
Foxa1 and Foxa2 regulate bile duct development in mice.
Li Z, White P, Tuteja G, Rubins N, Sackett S, Kaestner KH.
J Clin Invest. 2009 Jun;119(6):1537-45. doi: 10.1172/JCI38201. Epub 2009 May 11.
PMID 19436110
 
The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas.
Lin L, Miller CT, Contreras JI, Prescott MS, Dagenais SL, Wu R, Yee J, Orringer MB, Misek DE, Hanash SM, Glover TW, Beer DG.
Cancer Res. 2002 Sep 15;62(18):5273-9.
PMID 12234996
 
FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.
Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W, Carroll JS, Liu XS, Brown M.
Cell. 2008 Mar 21;132(6):958-70.
PMID 18358809
 
Prognosis of hormone-dependent breast cancers: implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet.
McCune K, Bhat-Nakshatri P, Thorat MA, Nephew KP, Badve S, Nakshatri H.
Cancer Res. 2010 Jan 15;70(2):685-96. Epub 2010 Jan 12.
PMID 20068169
 
SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains.
Minoo P, Hu L, Zhu N, Borok Z, Bellusci S, Groffen J, Kardassis D, Li C.
Nucleic Acids Res. 2008 Jan;36(1):179-88. Epub 2007 Nov 14.
PMID 18003659
 
Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm.
Monaghan AP, Kaestner KH, Grau E, Schutz G.
Development. 1993 Nov;119(3):567-78.
PMID 8187630
 
FOXA1 in breast cancer.
Nakshatri H, Badve S.
Expert Rev Mol Med. 2009 Mar 5;11:e8. (REVIEW)
PMID 19261198
 
FOXA1 is a potential oncogene in anaplastic thyroid carcinoma.
Nucera C, Eeckhoute J, Finn S, Carroll JS, Ligon AH, Priolo C, Fadda G, Toner M, Sheils O, Attard M, Pontecorvi A, Nose V, Loda M, Brown M.
Clin Cancer Res. 2009 Jun 1;15(11):3680-9. Epub 2009 May 26.
PMID 19470727
 
PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans.
Panowski SH, Wolff S, Aguilaniu H, Durieux J, Dillin A.
Nature. 2007 May 31;447(7144):550-5. Epub 2007 May 2.
PMID 17476212
 
Hepatocyte nuclear factor-3 alpha promoter regulation involves recognition by cell-specific factors, thyroid transcription factor-1, and autoactivation.
Peterson RS, Clevidence DE, Ye H, Costa RH.
Cell Growth Differ. 1997 Jan;8(1):69-82.
PMID 8993836
 
Forkhead box A1 transcriptional pathway in KRT7-expressing esophageal squamous cell carcinomas with extensive lymph node metastasis.
Sano M, Aoyagi K, Takahashi H, Kawamura T, Mabuchi T, Igaki H, Tachimori Y, Kato H, Ochiai A, Honda H, Nimura Y, Nagino M, Yoshida T, Sasaki H.
Int J Oncol. 2010 Feb;36(2):321-30.
PMID 20043065
 
Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.
Scharer CD, McCabe CD, Ali-Seyed M, Berger MF, Bulyk ML, Moreno CS.
Cancer Res. 2009 Jan 15;69(2):709-17.
PMID 19147588
 
Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo.
Sekiya T, Zaret KS.
Mol Cell. 2007 Oct 26;28(2):291-303.
PMID 17964267
 
Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer.
Song Y, Washington MK, Crawford HC.
Cancer Res. 2010 Mar 1;70(5):2115-25. Epub 2010 Feb 16.
PMID 20160041
 
Upstream stimulatory factor 2, a novel FoxA1-interacting protein, is involved in prostate-specific gene expression.
Sun Q, Yu X, Degraff DJ, Matusik RJ.
Mol Endocrinol. 2009 Dec;23(12):2038-47. Epub 2009 Oct 21.
PMID 19846536
 
Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis.
Thorat MA, Marchio C, Morimiya A, Savage K, Nakshatri H, Reis-Filho JS, Badve S.
J Clin Pathol. 2008 Mar;61(3):327-32. Epub 2007 Nov 23.
PMID 18037662
 
Genetic variation in the hepatocyte nuclear factor (HNF)-3alpha gene does not contribute to maturity-onset diabetes of the young in Japanese.
Yu L, Wei Q, Jin L, Nishigori H, Nishigori T, Tomura H, Fujita J, Yamada Y, Seino Y, Takeda J.
Horm Metab Res. 2001 Mar;33(3):163-6.
PMID 11355750
 

Citation

This paper should be referenced as such :
Nakshatri, H ; Badve, S
FOXA1 (forkhead box A1)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(4):327-330.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/FOXA1ID44403ch14q21.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(12;14)(q13;q21) ERBB3/FOXA1


External links

Nomenclature
Cards
AtlasFOXA1ID44403ch14q21.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)3169
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=FOXA1
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 18 17:36:48 CEST 2018

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.