Abstract A57: Functional synergy between the KLF6-SV1 and c-MYC oncogenes in driving prostate cancer metastasis in a novel mouse model of the disease
Authors: Izadmehr Sudeh , Lee Christine H. , Fernandez Heriberto , Hatami Raheleh , Kirschenbaum Alexander , Levine Alice C. , Difeo AnaLisa , Narla Goutham 
Published: May 2013

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related death among males in the United States. Many prostate tumors remain indolent and localized, while others result in metastatic and castrate-resistant disease. In order to uncover key molecular drivers that regulate the progression from indolent localized prostate cancer to lethal invasive and metastatic disease, the development of genetically relevant target driven mouse models is critical. Highly penetrant mouse models of this transition in which human disease relevant genes are the molecular drivers of disease progression are lacking. This transition is considered to be highly clinically relevant as our ability to distinguish between indolent disease and lethal metastatic forms of prostate cancer and has lead to either undertreatment of potentially poor behaving tumors or overtreatment of otherwise indolent disease. In addition, the paucity of biologically relevant models of advanced prostate cancer has hampered our ability to accurately and faithfully test novel therapeutic agents in relevant models of disease. To address this problem, we have developed a new murine model of PCa that combines transgenic overexpression of two genes known to be overexpressed in human prostate cancer (KLF6-SV1 and MYC). Overexpression of the c-Myc protein in the prostate of transgenic mice results in the development of both high-grade PIN and moderately differentiated prostate cancer. Interestingly, SV1 overexpression occurs late in disease progression with the highest protein expression occurring in locally invasive and metastatic human prostate cancers. In addition, SV1 overexpression in prostate cancer cell lines results in increased metastasis in vivo with no effect on local tumor growth. Combined, this data provides a strong experimental rationale for the characterization of the interactive and synergistic roles of these two disease relevant genes in the progression of moderately differentiated prostate cancer to poorly differentiated prostate cancer. Here we demonstrate for the first time that transgenic overexpression of MYC and SV1 results in invasive, metastatic prostate cancer with high penetrance in vivo. Pathological and molecular analyses identified a phenotype consistent with epithelial to mesenchymal transition (EMT), invasion and metastasis in this transgenic mouse model. Distant metastasis to several organs were observed and all double transgenic MYC and SV1 mice demonstrated evidence of capsular and stromal invasion by 36 weeks of age (n=14) as compared to none of the SV1 or MYC mice alone. To further understand the mechanism by which KLF6-SV1 and c-MYC regulate EMT, invasion, and metastasis, RWPE-1 cells, a non-tumorigenic prostate cell line that express low levels of KLF6-SV1 and c-MYC, were used to over-express c-MYC, KLF6-SV1 alone and in combination. Over-expression of these genes in RWPE-1, recapitulate our findings in vivo as assessed by a reduction in epithelial markers, such as E-cadherin and an increase in mesenchymal makers such as vimentin. These studies suggest that increased MYC and SV1 expression may drive a gene signature that is a prognostic indicator of aggressive and potentially metastatic human prostate cancer. In conclusion, this mouse model provides a novel tool for the functional evaluation of disease relevant genetic drivers of prostate cancer progression and should provide a roadmap for testing novel targeted molecular therapeutics to treat advanced prostate cancer.

Citation Format: Sudeh Izadmehr, Christine H. Lee, Heriberto Fernandez, Raheleh Hatami, Alexander Kirschenbaum, Alice C. Levine, AnaLisa Difeo, Goutham Narl. Functional synergy between the KLF6-SV1 and c-MYC oncogenes in driving prostate cancer metastasis in a novel mouse model of the disease [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A57.