Androgen receptor-independent function of FoxA1 in prostate cancer metastasis

Hong Jian Jin, Jonathan C. Zhao, Irene Ogden, Raymond Bergan, Jindan Yu

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensible 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 upregulated in localized prostate cancer wherein cell proliferation is the main feature, but is remarkably downregulated 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.

Original languageEnglish (US)
Pages (from-to)3725-3736
Number of pages12
JournalCancer Research
Volume73
Issue number12
DOIs
StatePublished - Jun 15 2013
Externally publishedYes

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Androgen Receptors
Prostatic Neoplasms
Neoplasm Metastasis
Cell Movement
Prostate
Epithelial-Mesenchymal Transition
Neoplasms
Mutation
Transcription Factors
Down-Regulation
Cell Proliferation
Gene Expression
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Androgen receptor-independent function of FoxA1 in prostate cancer metastasis. / Jin, Hong Jian; Zhao, Jonathan C.; Ogden, Irene; Bergan, Raymond; Yu, Jindan.

In: Cancer Research, Vol. 73, No. 12, 15.06.2013, p. 3725-3736.

Research output: Contribution to journalArticle

Jin, Hong Jian ; Zhao, Jonathan C. ; Ogden, Irene ; Bergan, Raymond ; Yu, Jindan. / Androgen receptor-independent function of FoxA1 in prostate cancer metastasis. In: Cancer Research. 2013 ; Vol. 73, No. 12. pp. 3725-3736.
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