ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Alvaro Aytes, Antonina Mitrofanova, Carolyn Waugh Kinkade, Celine Lefebvre, Ming Lei, Vanessa Phelan, H. Carl LeKaye, Jason A. Koutcher, Robert Cardiff, Andrea Califano, Michael M. Shen, Cory Abate-Shen

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Abstract

Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number37
DOIs
StatePublished - Sep 10 2013

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Phosphatidylinositol 3-Kinases
Prostatic Neoplasms
Neoplasm Metastasis
Prostate
Neoplasms
Up-Regulation
Epithelium
Alleles
Phenotype
Cell Line
Growth
Genes

ASJC Scopus subject areas

  • General

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ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. / Aytes, Alvaro; Mitrofanova, Antonina; Kinkade, Carolyn Waugh; Lefebvre, Celine; Lei, Ming; Phelan, Vanessa; LeKaye, H. Carl; Koutcher, Jason A.; Cardiff, Robert; Califano, Andrea; Shen, Michael M.; Abate-Shen, Cory.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 37, 10.09.2013.

Research output: Contribution to journalArticle

Aytes, Alvaro ; Mitrofanova, Antonina ; Kinkade, Carolyn Waugh ; Lefebvre, Celine ; Lei, Ming ; Phelan, Vanessa ; LeKaye, H. Carl ; Koutcher, Jason A. ; Cardiff, Robert ; Califano, Andrea ; Shen, Michael M. ; Abate-Shen, Cory. / ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 37.
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