NEXT-GENERATION MOUSE MODELS FOR STUDYING PROSTATE CANCER INITIATION AND PROGRESSION

Background: Mouse models have provided numerous insights into the molecular mechanisms that underlie the initiation and progression of prostate cancer. More recently, mouse models have been utilized to analyze the effects of targeted therapeutics and are now being used in preclinical studies of chemoprevention as well as combined chemotherapies. Despite these successes, there are significant limitations of current mouse models for modeling prostate cancer progression as well as the effects of therapeutic interventions. These limitations can be overcome by the use of sophisticated new methods to manipulate gene expression in mice.Objective: In this application, we will develop 'next-generation' mouse models of prostate cancer that feature inducible and regulatable gene expression in the prostate. Specifically, we will generate in vivo systems in which targeted gene deletion or activation is inducible in the adult prostate epithelium, mimicking the adult somatic origin of human cancer. We will also develop systems in which oncogene expression is reversible, thereby modeling the consequences of effective targeted therapeutics. Finally, we plan to develop reversible systems in which oncogene expression is not dependent on androgen signaling, thereby enabling the direct evaluation of hormonal therapies independent of androgen status.In our proposed studies, we will utilize these methodologies to generate autochthonous mouse models that are based on genetic changes that occur during the pathogenesis of human prostate cancer, including overexpression of the Erg transcription factor or gain-of-function for androgen receptor or loss-of-function for the Pten tumor suppressor in combination with downregulation of E-cadherin, leading to an epithelial-mesenchymal transition (EMT). The resulting mouse models will be ideally suited for functional characterization of these genes and/or associated pathways as targets for therapeutic intervention. In particular, these studies will provide essential reagents for future translational investigations of the efficacy of targeted therapies for advanced prostate cancer independent of hormonal status.Specific Aims: In our preliminary work, we have successfully implemented tetracycline-regulatable as well as inducible Cre recombinase strategies in the mouse prostate epithelium. Consequently, we are now ideally suited to create 'next-generation' mouse models of prostate cancer that utilize reversible and inducible methodologies for investigation of fundamental issues regarding cancer progression in vivo. The specific aims are to (1) investigate oncogene addiction using an androgen-independent reversible expression system to model the effects of targeted therapies, and (2) analyze an inducible mouse model to examine the role of the EMT in prostate cancer progression.Study Design: We will utilize a three-component tetracycline-regulatable system with an androgen-independent promoter to drive oncogene expression in the transgenic mouse prostate, which will allow investigation of therapeutic approaches in combination with androgen deprivation. In particular, we will utilize this system to investigate the consequences of Ets transcription factor overexpression as well as the effects of expressing a mutant androgen receptor. In addition, we will examine the consequences of inducing an EMT through deletion of E-cadherin in the adult prostate epithelium in the context of a prostate cancer model.Innovation: These studies are highly innovative because they utilize recently developed technologies of reversible gene expression and inducible gene targeting in the prostate epithelium, which allow increasingly accurate modeling of human prostate cancer in mice. Furthermore, our transgenic mouse system will permit the modeling of therapeutic interventions in the context of manipulations of androgen status, which has not been feasible using previous approaches.Impact: Our proposed studies will provide important new model systems for future preclinical studies in mice and will also provide mechanistic insights into the consequences of Ets transcription factor and androgen receptor function in prostate cancer, as well as the role of the EMT in vivo.