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FOXF1 (forkhead box F1)

Written2012-02Pang-Kuo Lo
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, USA

(Note : for Links provided by Atlas : click)


Other aliasACDMPV
LocusID (NCBI) 2294
Atlas_Id 40628
Location 16q24.1  [Link to chromosome band 16q24]
Location_base_pair Starts at and ends at bp from pter
Local_order According to the NCBI Map Viewer, genes flanking FOXF1 in centromere to telomere direction on 16q24 are:
- LOC401864 (chloride intracellular channel 1 pseudogene);
- FLJ34515 (uncharacterized LOC400550);
- FOXF1 (forkhead box F1);
- RPL7AP63 (ribosomal protein L7a pseudogene 63);
- MTHFSD (methenyltetrahydrofolate synthetase domain containing);
- FLJ30679 (uncharacterized protein FLJ30679);
- FOXC2 (forkhead box C2, mesenchyme forkhead 1);
- FOXL1 (forkhead box L1).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note This gene encodes a transcription factor of the forkhead family which is characterized by a unique forkhead DNA-binding domain. The function of this gene is implicated in regulation of embryonic development and organ morphogenesis. The cellular role of this gene has been found to regulate cell cycle progression and epithelial-to-mesenchymal transition (EMT). Dysregulation of FOXF1 gene expression has been linked to various cancers and genomic deletions or mutations at this gene locus have been discovered to be associated with congenital abnormalities. The role of FOXF1 in cancer has been proposed to act as either an oncogene or a tumor suppressor gene depending on cell types and disease stages.


  The pink boxes indicate the open reading frame and the sky blue boxes indicate the untranslated mRNA region.
Description The FOXF1 gene is composed of two exons with sizes of 1022 and 1540 bp, respectively.
Transcription The FOXF1 gene expresses 2,58 kb mRNA with the 1140 bp open reading frame.


Description Human FOXF1 is a 379 amino acid protein functioning as a transcription factor. The FOXF1 protein contains a forkhead domain (or called winged helix, 48-125 amino acids) engaged in binding to B-DNA (Kim et al., 2005). According to the information from the NCBI reference sequence NP_001442 for the FOXF1 protein, amino acids 84, 85, 94, 97, 98 and 118 are involved in interaction with nucleotides of DNA. In addition to the forkhead DNA-binding domain, the C-terminal of FOXF1 possesses characteristics of the transcriptional activation domain (Mahlapuu et al., 1998). However, its region has not yet been convincingly defined. The studies have shown that FOXF1 transcripitionally modulates expression of tissue-specific genes (e.g. lung, intestine) (Hellqvist et al., 1996; Mahlapuu et al., 1998; Costa et al., 2001; Ormestad et al., 2006; Madison et al., 2009).
Expression According to published literature, the FOXF1 transcription factor has been identified to be highly expressed in the normal human prostate transition zone and benign prostate hyperplasia (BPH), but decreasingly expressed in prostate cancer (Watson et al., 2004; van der Heul-Nieuwenhuijsen et al., 2009). FOXF1 is expressed in normal breast ductal epithelial cells and basal-like breast cancer cells, but is silenced in luminal breast cancer cells mainly through the epigenetic mechanism (Lo et al., 2010; Nilsson et al., 2010). FOXF1 expression is detected in cancer-associated fibroblasts of human lung cancer and its expression is associated with activation of hedgehog signaling (Saito et al., 2010). Upregulation of FOXF1 expression is also found in PTCH1-associated rhabdomyosarcoma (Wendling et al., 2008).
Localisation Localized in the nucleus.
Function The biological roles of forkhead box protein F1 were mostly studied in murine genetic models and are linked to regulate embryogenesis and organogenesis (Mahlapuu et al., 2001a; Costa et al., 2001; Kalinichenko et al., 2001; Mahlapuu et al., 2001b; Kalinichenko et al., 2002; Lim et al., 2002; Ormestad et al., 2006; Astorga and Carlsson, 2007; Yu et al., 2010). However, the functional roles of the human FOXF1 protein are still largely unknown. Some of published studies indicate that FOXF1 participates in regulation of the following normal and abnormal cellular processes:
The role of FOXF1 in an Epithelial-to-Mesenchymal Transition (EMT): FOXF1 has been found to be a direct repressed target of nuclear factor 1-C2 (NF1-C2) whose expression is lost during mammary tumor progression and is almost absent from lymph node metastases (Nilsson et al., 2010). FOXF1 is preferentially expressed in breast cancer cell lines with a mesenchymal phenotype and its ectopic overexpression in mammary epithelial cells induces mesenchymal traits, increased invasiveness in vitro and enhanced xenograft tumorigenesis in vivo (Nilsson et al., 2010). Hence FOXF1 is proposed to promote invasion and metastasis.
The oncogenic role of FOXF1 in lung cancer-associated fibroblasts: FOXF1 is found to be expressed in cancer-associated fibroblasts of human lung cancer and associated with activation of hedgehog signaling (Saito et al., 2010). Gain- and loss-of-function studies of FOXF1 in fibroblasts show that FOXF1 is implicated in regulating the contractility of fibroblasts and abilities of fibroblasts to produce hepatocyte growth factor as well as fibroblast growth factor-2 and to stimulate migration of lung cancer epithelial cells (Saito et al., 2010). The expression status of FOXF1 in fibroblasts positively correlates with the ability of fibroblasts to enhance xenograft tumor growth (Saito et al., 2010). These findings suggest that hedgehog-dependent FOXF1 is a clinically relevant factor to grant oncogenic abilities to cancer-associated fibroblasts for propelling development of lung cancer.
The role of FOXF1 in regulation of cell cycle progression: FOXF1 has been identified as a target of epigenetic inactivation in breast cancer (Lo et al., 2010). Ectopic reexpression of FOXF1 in FOXF1-negative breast cancer cells induces cell growth arrest by inhibition of the CDK2-RB-E2F cascade (Lo et al., 2010). FOXF1 knockdown studies of FOXF1-expressing breast cancer epithelial cells revealed that FOXF1 is indispensable for maintaining the stringency of DNA replication and genomic stability by negatively modulating expression of E2F target genes which are involved in promoting the progression of S and G2 phases (Lo et al., 2010; Lo et al., 2012). These lines of evidence suggest that FOXF1 is an epigenetically silenced tumor suppressor gene in breast cancer, which is essential for maintaining genomic stability by regulating the stringency of DNA replication.
Homology - Pan troglodytes (chimpanzee), FOXF1 (XP_523449.2, 535 aa), 99% identity;
- Canis lupus (dog), FOXF1 (XP_546792.2, 354 aa), 95% identity;
- Bos taurus (cattle), FOXF1 (XP_603148.3, 382 aa), 96% identity;
- Mus musculus (mouse), Foxf1a (NP_034556.1, 353 aa), 94% identity;
- Gallus gallus (chicken), FOXF1 (XP_414186.2, 368 aa), 91% identity;
- Danio rerio (zebrafish), Foxf1 (NP_001073655.1, 380 aa), 81% identity.


Note Four different heterozygous mutations (frameshift, nonsense, and non-stop) have been identified in the FOXF1 gene in unrelated patients with sporadic ACD/MPV (alveolar capillary dysplasia with misalignment of pulmonary veins) and MCA (multiple congenital anomalies) (Stankiewicz et al., 2009). The point mutations identified in the FOXF1 gene are associated with bowel malrotation, annular pancreas, duodenal stenosis, congenital short bowel, small omphalocele and Meckel's diverticulum (Stankiewicz et al., 2009).

Implicated in

Entity Breast cancer
Oncogenesis Loss or downregulation of FOXF1 expression is found to be associated with FOXF1 promoter hypermethylation in breast cancer cell lines and in breast invasive ductal carcinomas (Lo et al., 2010). According to analysis of 117 invasive ductal carcinoma (IDC) cases, FOXF1 promoter was hypermethylated in 37,6% of examined IDC cases, which was associated with high tumor grade (Lo et al., 2010). The gain- and loss-of-function studies of FOXF1 in breast cancer cells indicate that FOXF1 plays an imperative role in maintaining the stringency of DNA replication for sustaining genomic stability (Lo et al., 2010; Lo et al., 2012). These clinical correlation and cellular functional studies suggest that FOXF1 is a potential tumor suppressor gene which is epigenetically silenced in breast cancer.
Entity Lung cancer
Oncogenesis Immunohistochemical (IHC) staining of FOXF1 is found to be positive in nuclei of lung cancer-associated fibroblasts (CAFs) (Saito et al., 2010). The frequency of positivity of FOXF1 IHC staining in CAFs is 110 (44,5%) out of 247 cases examined (Saito et al., 2010). The IHC studies exhibited stronger FOXF1 staining in the stromal cells adjacent to lung tumor cells compared with those further apart from the tumor cells. FOXF1 expression in CAFs is not significantly associated with any particular histologic subtypes of lung cancer and also does not correlate with survival in the overall population. However, lung cancer patients from the female population or from the large cell lung cancer population show positive correlation between FOXF1 expression in CAFs and predicted poor prognosis (Saito et al., 2010). These IHC studies, in combination with in vitro functional studies of FOXF1 in fibroblasts (Saito et al., 2010), suggest that FOXF1 plays an oncogenic role in CAF-stimulated lung tumorigenesis.
Entity Prostate cancer
Oncogenesis FOXF1 expression is lost or downregulated in prostate cancer compared with normal prostate tissue (Watson et al., 2004; van der Heul-Nieuwenhuijsen et al., 2009). This suggests that FOXF1 is a putative tumor suppressor gene in prostate cancer.
Entity Nevoid basal cell carcinoma syndrome
Disease Patients with nevoid basal cell carcinoma syndrome (NBCCS) carry germline mutation in the tumor suppressor gene Patched 1 (PTCH1) and are predisposed to develop basal cell carcinoma (BCC), medulloblastoma (MB) and rhabdomyosarcoma (RMS).
Oncogenesis FOXF1 expression is found to be aberrantly upregulated in NBCCS-associated tumors compared with the respective non-neoplastic tissue (Wendling et al., 2008). Overexpression of FOXF1 is accompanied by increased levels of the hedgehog target Gli1 as well as the putative FOXF1 targets Bmi1 and Notch2 in NBCCS-associated tumors (Wendling et al., 2008). These findings suggest a key role for FOXF1 in hedgehog-associated tumorigenesis.
Entity Idiopathic interstitial pneumonias
Disease The idiopathic interstitial pneumonias (IIP) represent a set of diffuse parenchymal lung disorders and are sub-classified into usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonitis (NSIP) and the fibrotic variant of NSIP (NSIP-F).
Examination of surgical and autopsy specimens from 13 patients with either UIP or NSIP-F has revealed that all of UIP cases exhibited a pattern of strong SHH (a hedgehog ligand) expression with weak FOXF1 expression and NSIP-F cases displayed a complementary expression of SHH and FOXF1 (Coon et al., 2006). These studies suggest that morphogenetic genes (e.g. FOXF1) may participate differentially in the pathogenesis of UIP and NSIP-F.
Entity Alveolar capillary dysplasia with misalignment of pulmonary veins
Disease Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Infants with ACD/MPV develop respiratory distress and severe pulmonary hypertension within the first two days of life. ACD/MPV-affected infants mostly can not survive within the first month of life due to no sustained response to supportive measures and respiratory failure. More than 80% of infants with ACD/MPV have additional malformations occurring in the cardiac, gastrointestinal, and genitourinary systems. Intestinal malrotation is the most commonly observed of these anomalies, and hypoplastic left heart together with hypoplasia or coarctation of the aortic arch are the most common associated cardiovascular abnormalities. Of almost 200 reported ACD/MPV cases, approximately 10% have a familial association.
Four distinct heterozygous mutations (frameshift, nonsense, and no-stop) were identified in the FOXF1 gene in unrelated 18 patients with sporadic ACD/MPV and MCA (Stankiewicz et al., 2009), suggesting that an impairment in the FOXF1 function might lead to these observed developmental disorders.


Hedgehog induction of murine vasculogenesis is mediated by Foxf1 and Bmp4.
Astorga J, Carlsson P.
Development. 2007 Oct;134(20):3753-61. Epub 2007 Sep 19.
PMID 17881493
Differential epithelial expression of SHH and FOXF1 in usual and nonspecific interstitial pneumonia.
Coon DR, Roberts DJ, Loscertales M, Kradin R.
Exp Mol Pathol. 2006 Apr;80(2):119-23. Epub 2006 Jan 30.
PMID 16448649
Transcription factors in mouse lung development and function.
Costa RH, Kalinichenko VV, Lim L.
Am J Physiol Lung Cell Mol Physiol. 2001 May;280(5):L823-38. (REVIEW)
PMID 11290504
Differential activation of lung-specific genes by two forkhead proteins, FREAC-1 and FREAC-2.
Hellqvist M, Mahlapuu M, Samuelsson L, Enerback S, Carlsson P.
J Biol Chem. 1996 Feb 23;271(8):4482-90.
PMID 8626802
Haploinsufficiency of the mouse Forkhead Box f1 gene causes defects in gall bladder development.
Kalinichenko VV, Zhou Y, Bhattacharyya D, Kim W, Shin B, Bambal K, Costa RH.
J Biol Chem. 2002 Apr 5;277(14):12369-74. Epub 2002 Jan 23.
PMID 11809759
Functional characterization of evolutionarily conserved DNA regions in forkhead box f1 gene locus.
Kim IM, Zhou Y, Ramakrishna S, Hughes DE, Solway J, Costa RH, Kalinichenko VV.
J Biol Chem. 2005 Nov 11;280(45):37908-16. Epub 2005 Sep 6.
PMID 16144835
Fusion of lung lobes and vessels in mouse embryos heterozygous for the forkhead box f1 targeted allele.
Lim L, Kalinichenko VV, Whitsett JA, Costa RH.
Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L1012-22.
PMID 11943666
The p53-p21WAF1 checkpoint pathway plays a protective role in preventing DNA rereplication induced by abrogation of FOXF1 function.
Lo PK, Lee JS, Sukumar S.
Cell Signal. 2012 Jan;24(1):316-24. Epub 2011 Sep 22.
PMID 21964066
FoxF1 and FoxL1 link hedgehog signaling and the control of epithelial proliferation in the developing stomach and intestine.
Madison BB, McKenna LB, Dolson D, Epstein DJ, Kaestner KH.
J Biol Chem. 2009 Feb 27;284(9):5936-44. Epub 2008 Dec 2.
PMID 19049965
The forkhead transcription factor Foxf1 is required for differentiation of extra-embryonic and lateral plate mesoderm.
Mahlapuu M, Ormestad M, Enerback S, Carlsson P.
Development. 2001b Jan;128(2):155-66.
PMID 11124112
Nuclear Janus-activated kinase 2/nuclear factor 1-C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing Forkhead box F1.
Nilsson J, Helou K, Kovacs A, Bendahl PO, Bjursell G, Ferno M, Carlsson P, Kannius-Janson M.
Cancer Res. 2010 Mar 1;70(5):2020-9. Epub 2010 Feb 9.
PMID 20145151
Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production.
Ormestad M, Astorga J, Landgren H, Wang T, Johansson BR, Miura N, Carlsson P.
Development. 2006 Mar;133(5):833-43. Epub 2006 Jan 26.
PMID 16439479
Forkhead box F1 regulates tumor-promoting properties of cancer-associated fibroblasts in lung cancer.
Saito RA, Micke P, Paulsson J, Augsten M, Pena C, Jonsson P, Botling J, Edlund K, Johansson L, Carlsson P, Jirstrom K, Miyazono K, Ostman A.
Cancer Res. 2010 Apr 1;70(7):2644-54. Epub 2010 Mar 16.
PMID 20233876
Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations.
Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, Ou Z, Wiszniewska J, Driscoll DJ, Maisenbacher MK, Bolivar J, Bauer M, Zackai EH, McDonald-McGinn D, Nowaczyk MM, Murray M, Hustead V, Mascotti K, Schultz R, Hallam L, McRae D, Nicholson AG, Newbury R, Durham-O'Donnell J, Knight G, Kini U, Shaikh TH, Martin V, Tyreman M, Simonic I, Willatt L, Paterson J, Mehta S, Rajan D, Fitzgerald T, Gribble S, Prigmore E, Patel A, Shaffer LG, Carter NP, Cheung SW, Langston C, Shaw-Smith C.
Am J Hum Genet. 2009 Jun;84(6):780-91. Epub 2009 Jun 4.
PMID 19500772
Integration of high-resolution array comparative genomic hybridization analysis of chromosome 16q with expression array data refines common regions of loss at 16q23-qter and identifies underlying candidate tumor suppressor genes in prostate cancer.
Watson JE, Doggett NA, Albertson DG, Andaya A, Chinnaiyan A, van Dekken H, Ginzinger D, Haqq C, James K, Kamkar S, Kowbel D, Pinkel D, Schmitt L, Simko JP, Volik S, Weinberg VK, Paris PL, Collins C.
Oncogene. 2004 Apr 22;23(19):3487-94.
PMID 15007382
Characteristic overexpression of the forkhead box transcription factor Foxf1 in Patched-associated tumors.
Wendling DS, Luck C, von Schweinitz D, Kappler R.
Int J Mol Med. 2008 Dec;22(6):787-92.
PMID 19020777
Haploinsufficiencies of FOXF1 and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease.
Yu S, Shao L, Kilbride H, Zwick DL.
Am J Med Genet A. 2010 May;152A(5):1257-62.
PMID 20425831
Gene expression of forkhead transcription factors in the normal and diseased human prostate.
van der Heul-Nieuwenhuijsen L, Dits NF, Jenster G.
BJU Int. 2009 Jun;103(11):1574-80. Epub 2009 Feb 11.
PMID 19220249


This paper should be referenced as such :
Lo, PK
FOXF1 (forkhead box F1)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(7):467-470.
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External links

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)2294
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
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