Molecular Basis of Carcinogenesis in Rodent Models of Prostate Cancer

Abstract

Recurrent genomic alterations in aggressive primary and metastatic castration resistant prostate cancer (mCRPC) have been identified through intensive sequencing efforts of clinical tumor samples over the last two decades. A combination of recurrent genomic alterations is a ubiquitous feature of metastatic disease. Disease progression in transgenic mouse models of prostate cancer support this observation: mice with single genomic alterations fail to develop large aggressive primary tumors, or do so with long latency and incomplete penetrance, whereas mice with combined genomic alterations have higher rates of aggressive primary tumor formation and metastasis, with shorter disease latency. Cooperativity between multiple recurrent genomic alterations is poorly understood. We used the BMPC mouse model of mCRPC to address this issue. BMPC prostate tumors are driven by combined MYC activation and loss of tumor suppressor Pten, which are the best predictors of poor prognosis in the human disease. We used a bulk RNAseq approach to characterize transcriptomic changes in prostatic intraepithelial neoplasias (PIN) in mice with MYC activation, PTEN loss, and the combination thereof in BMPC PIN. The combination of MYC activation and Pten loss synergistically activates genes that promote proliferation, inhibit apoptosis, promote immune cell evasion, and modulate the cell constituency in prostatic lobes with PIN. We then characterized disease progression in the BMP53 rat model of prostate cancer, which develops CRPC driven by MYC activation and loss of tumor suppressor Tp53. BMP53 rats form multifocal carcinogenic lesions similar to the human disease. Adenocarcinomas in BMP53 rats were negative for Pten by IHC, which we found was secondary to genomic Pten loss. These data suggest that MYC activation and Pten loss is a more potent driver of disease than MYC activation and Tp53 loss. Our results demonstrate MYC activation and Pten loss synergistically activate biological pathways that are dormant in the context of either event alone, and in the context of genomic instability secondary to Tp53-nullity, genomic Pten loss is a requisite step for aggressive carcinogenesis in the rat prostate epithelium.