FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensable for the lineage-specific gene expression of the prostate.
To date, there have been conflicting reports on the role of FoxA1 in prostate cancer progression and prognosis. With recent discoveries of recurrent FoxA1 mutations in human prostate tumors, comprehensive understanding of FoxA1 function has become very important. Here, through genomic analysis we reveal that FoxA1 regulates two distinct oncogenic processes via disparate mechanisms. FoxA1 induces cell growth requiring the AR pathway. On the other hand, FoxA1 inhibits cell motility and epithelial-to-mesenchymal transition (EMT) through AR-independent mechanism directly opposing the action of AR signaling. Using orthotopic mouse models we further show that FoxA1 inhibits prostate tumor metastasis in vivo. Concordant with these contradictory effects on tumor progression, FoxA1 expression is slightly up-regulated in localized prostate cancer wherein cell proliferation is the main feature, but is remarkably down-regulated when the disease progresses to metastatic stage for which cell motility and EMT are essential. Importantly, recently identified FoxA1 mutants have drastically attenuated ability in suppressing cell motility. Taken together, our findings illustrate an AR-independent function of FoxA1 as a metastasis inhibitor and provide a mechanism by which recurrent FoxA1 mutations contribute to prostate cancer progression.
Written by:
Jin HJ, Zhao JC, Ogden I, Bergan R, Yu J. Are you the author?
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine.
Reference: Cancer Res. 2013 Mar 28. Epub ahead of print.
doi: 10.1158/0008-5472.CAN-12-3468
PubMed Abstract
PMID: 23539448
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