Abstract
Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAFV600E–a mutation found in ∼10% of human prostate tumors–was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAFV600E in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAFV600E is not required for its maintenance.
Highlights
Prostate cancer (PCA) is the most common malignancy affecting men over age of 65
RtTA is known to potently drive expression of a transgene linked to a Tet-responsive promoter and is a highly specific read-out of the Tet-driven transgene (BRAF* in this case) expression. rtTA transcripts were not detected in non-transgenic wild-type prostate gland, yet were abundant in iBRAF* transgenic prostates exposed to doxycycline (Figure 1B), in the luminal cells (Figure 1B, zoom-in panel, see arrows)
To further refine localization of transgene expression in the epithelium and determine whether the transgene is expressed in the basal cell compartment, we performed serial p63 IHC and rtTA RNA in situ hybridization (RISH) in 8-week-old male iBRAF* prostate glands induced on doxycycline (Figure 1C)
Summary
Prostate cancer (PCA) is the most common malignancy affecting men over age of 65. Initially responsive to hormonal ablation therapy, PCA invariably recur and evolve to become lethal androgen-independent (AI) disease. In a study of Korean patients, KRAS activating mutations were detected in 7% of cases and another 10% harbored the BRAFV600E activating mutation[25] In consonance with these mutation data, Raf expression is often found to be elevated and B-Raf inhibitor reduced in human prostate tumors[26]. ETV1/ER85, a partner in the high frequency TMPRSS2:ETV1 chromosomal fusion event in human prostate cancer, is a downstream target of RAS-RAF-MAPK signaling[27]. These reinforcing, albeit correlative, data have implicated activated RAS-RAF-MAPK signaling in the prostate cancer genesis and progression
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