B-raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer

Jingqiang Wang, Takashi Kobayashi, Nicolas Floc'h, Carolyn Waugh Kinkade, Alvaro Aytes, David Dankort, Celine Lefebvre, Antonina Mitrofanova, Robert Cardiff, Martin McMahon, Andrea Califano, Michael M. Shen, Cory Abate-Shen

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Both the PI3K → Akt → mTOR and mitogen-activated protein kinase (MAPK) signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and extracellular signal-regulated kinase 1/2 (ERK1/2) MAPK signaling is activated by inducible expression of a BRAFV600E oncogene. These tissue-speci fic compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow, and lungs where they form overt metastases in approximately 30% of the cases. Activation of PI3K → Akt → mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K → Akt → mTOR and ERK1/2 MAPK signaling pathways.

Original languageEnglish (US)
Pages (from-to)4765-4776
Number of pages12
JournalCancer Research
Volume72
Issue number18
DOIs
StatePublished - Sep 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, J., Kobayashi, T., Floc'h, N., Kinkade, C. W., Aytes, A., Dankort, D., Lefebvre, C., Mitrofanova, A., Cardiff, R., McMahon, M., Califano, A., Shen, M. M., & Abate-Shen, C. (2012). B-raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer. Cancer Research, 72(18), 4765-4776. https://doi.org/10.1158/0008-5472.CAN-12-0820