B-Raf Activation Cooperates with PTEN Loss to Drive c-Myc Expression in Advanced Prostate Cancer

and Center for Comparative Medicine and Department of Pathology, School of Medicine, University of California, Davis, California.
Cancer Research (Impact Factor: 9.33). 07/2012; 72(18):4765-4776. DOI: 10.1158/0008-5472.CAN-12-0820
Source: PubMed


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 BRAF(V600E) oncogene. These tissue-specific 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. Cancer Res; 72(18); 4765-76. ©2012 AACR.

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Available from: Martin McMahon, Nov 23, 2015
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    • "p70S6K acts downstream of the Akt/mTOR pathway and is a well-known regulator of cell growth during development and in adult diseases such as cardiac hypertrophy (Ahuja et al., 2007; Crackower et al., 2002; Fingar et al., 2002; Pereira et al., 2009; Shima et al., 1998; Shioi et al., 2000; Takano et al., 1996). Recent studies have implicated that the Akt/mTOR/ p70S6K pathway and MYC act coordinately in different cellular events including cell proliferation and metabolism (Schramm et al., 2012; Wang et al., 2012; Ward and Thompson, 2012). Our results show that MYC can regulate expression of p70S6K and thus provide clues as to how exactly MYC interacts with the Akt/mTOR/p70S6K pathway. "
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