Disease relevance of FOXA1

• In this study, we analyzed the activities and expression pattern of FOXA1 in breast cancer [1].
• Analysis of FOXA1 expression in breast tissue arrays revealed significantly higher expression in pure ductal carcinomas in situ compared to invasive ductal carcinomas (IDC); and in IDC, high expression of FOXA1 was associated with favorable prognostic factors [1].
• The transcription factor Forkhead-box A1 (Foxa1), a member of the FOX class of transcription factors, has been implicated in the pathogenesis of lung, esophageal and prostate cancers [1].
• FOXA1 gene is amplified and over-expressed in esophageal and lung cancer [2].
• The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas [3].
• We show that FOXA1 is overexpressed in human anaplastic thyroid carcinomas (ATC) [4].

High impact information on FOXA1

• Further, FOXA1 was identified as a downstream target of GATA-3 in the mammary gland [5].
• From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response [6].
• The promoters were linked to known ERalpha targets but also to many genes not directly associated with the estrogenic response, including the transcriptional factor FOXA1, whose expression correlates with the presence of ERalpha in breast tumors [6].
• Taken together, these results define a paradigm for estrogen action in breast cancer cells and suggest that regulation of gene expression by nuclear receptors can be compartmentalized into unique transcriptional domains by means of licensing of their activity to cofactors such as FOXA1 [6].
• Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins [7].

Chemical compound and disease context of FOXA1

• FOXA1, a winged-helix transcription factor belonging to the forkhead family, is one among them as it is expressed predominantly in luminal type A breast cancer, which is characterized by the presence of estrogen receptor-alpha (ERalpha) with favorable prognosis [8].
• Foxa1 was strongly expressed in areas of prostatic intraepithelial neoplasia (PIN) in both the androgen dependent 12T-7f and in the metastatic, androgen independent 12T-10 LADY models [9].
• FOXA1 expression correlates with luminal subtype A breast cancer and it is significant predictor of cancer-specific survival in patients with ER-positive tumors [10].

Biological context of FOXA1

• We have recently identified transcriptional activation of p27 by FOXA1 [1].
• In transient transfection reporter assays, FOXA1 could activate the p27(Kip1) promoter [11].
• Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27(Kip1) promoter, but this binding was lost upon mutation of this FOXA1 binding site [11].
• However, by controlling differentiation and by regulating the expression of cell cycle inhibitor p27kip1 and the cell adhesion molecule E-cadherin, FOXA1 may prevent metastatic progression of luminal type A breast cancer [8].
• Insight into the unique molecular basis of Foxa function has been obtained from recent genetic and genomic data, which identify the Foxa proteins as 'pioneer factors' whose binding to promoters and enhancers enable chromatin access for other tissue-specific transcription factors [12].

Anatomical context of FOXA1

• Forced expression of FOXA1 inhibited clonal growth of breast cancer cell lines, and FOXA1 levels inversely correlated with growth stimuli [1].
• Hepatocyte nuclear factors 3 alpha, beta, and gamma (Foxa-1, -2, and -3) are transcriptional activators of important metabolic genes in the liver that are suppressed by the actions of insulin [7].
• Foxa1 and Foxa2 cooperate to establish competence in foregut endoderm and are required for normal development of endoderm-derived organs such as the liver, pancreas, lungs, and prostate [12].
• In post-natal life, members of the Foxa family control glucose metabolism through the regulation of multiple target genes in the liver, pancreas, and adipose tissue [12].
• CONCLUSIONS: Foxa proteins represent epithelial cell markers in the murine prostate gland [13].

Associations of FOXA1 with chemical compounds

• Specific Interactions of the Wing Domains of FOXA1 Transcription Factor with DNA [14].
• The sequence immediately downstream of the AP-1 element contained a binding site for HNF-3 (FOXA), and simultaneous mutation of this site (fox-d) and an upstream FoxA binding site (-277, fox-u) caused a 4-fold reduction in chloramphenicol acetyltransferase activity [15].
• To determine whether the wing domains contribute to stable DNA binding, we assessed complexes of FOXA with high and lower affinity DNA target sites by hydroxyl radical footprinting and site-directed mutagenesis [14].

Physical interactions of FOXA1

• Mutation of the FOXA1 DNA-binding site in the p27(Kip1) promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1 [11].

Regulatory relationships of FOXA1

• The half-life of FOXA1 was increased when coexpressed with BRCA1 [11].
• Restriction enzyme accessibility assays reveal that HNF3alpha promotes the assembly of an open chromatin structure at the AFP promoter [16].

Other interactions of FOXA1

• Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27(Kip1) promoter [11].
• Mutational analysis of the enhancer demonstrates that NF1/CTF cooperates with HNF3 alpha to induce enhancer activity [17].
• Combined, these functional and structural data suggest that chromatin assembly establishes a barrier to block inappropriate expression of AFP in non-hepatic tissues and that tissue-specific factors, such as HNF3alpha, are required to alleviate the chromatin-mediated repression [16].

Analytical, diagnostic and therapeutic context of FOXA1

• RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues [11].
• Foxa protein expression was investigated in the LPB-Tag LADY mouse prostate cancer models, in human prostate cancer specimens, and various prostate cancer cell lines using Western blot and immunostaining analysis [9].
• Prostate tissue from pre-pubertal, pubertal, and adult mice were analyzed by Western blot and RT-PCR analysis for Foxa1, a2, and a3 expression [13].
• Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice [9].

References