Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers. Issue 11 (29th September 2018)

• Record Type: Journal Article
• Authors: Neff, Robert; Rush, Craig M.; Smith, Blair; Backes, Floor J.; Cohn, David E.; Goodfellow, Paul J.
• Is Part Of: International journal of cancer. Volume 143:Issue 11(2018)
• Page Start: 2955
• Page End: 2961
• Publication Date: 2018-09-29
• Subjects: endometrial cancer -- forkhead box protein FOXA2 -- tumor suppressor; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31784
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : FOXA2, a member of the forkhead family of DNA‐binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N‐terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E‐cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C‐terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E‐cadherin ( CDH1 ) expression and E‐cadherin's potential role in epithelial‐to‐mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT‐PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression. Abstract : What's new? FOXA2, a member of the forkhead family of DNA‐binding proteins that is frequently mutated in uterine cancers, is considered to be a driver gene functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, remain to be elucidated. Here, the authors determined that FOXA2 mutations result in altered protein abundance and transcription factor activity. Importantly, expression of the known transcriptional target E‐cadherin, which may play a role in epithelial‐to‐mesenchymal transition in a wide range of cancers, is reduced in primary uterine tumors with FOXA2 mutations. The study provides further evidence that FOXA2 is a haploinsufficient tumor suppressor.