title: B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer.
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 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.
authors: Department of Urology and Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10031, USA.
authors: Jingqiang
authors: J
authors: Wang
authors: Takashi
authors: T
authors: Kobayashi
authors: Nicolas
authors: N
authors: Floc'h
authors: Carolyn Waugh
authors: CW
authors: Kinkade
authors: Alvaro
authors: A
authors: Aytes
authors: David
authors: D
authors: Dankort
authors: Celine
authors: C
authors: Lefebvre
authors: Antonina
authors: A
authors: Mitrofanova
authors: Robert D
authors: RD
authors: Cardiff
authors: Martin
authors: M
authors: McMahon
authors: Andrea
authors: A
authors: Califano
authors: Michael M
authors: MM
authors: Shen
authors: Cory
authors: C
authors: Abate-Shen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D020869:Gene Expression Profiling; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase