Prostate cancer (CaP) is the leading cancer diagnosis in men in the United States, with new cases for 2012 estimated at 241,740 and over 28,000 estimated annual deaths from the disease

914 INTRODUCTION Prostate cancer (CaP) is the leading cancer diagnosis in men in the United States, with new cases for 2012 estimated at 241,740 and over 28,000 estimated annual deaths from the disease (http://www.cancer.gov/cancertopics/types/prostate). Clinical cures are achieved in approximately 80% of patients presenting with localized disease; however, once metastasis occurs, response to second-line therapy, usually treatment with an androgen receptor agonist such as bicalutamide, is only 25%, with the response duration lasting for only a few months. Although multiple studies have documented a link between mutations in Tp53 and disease progression in individuals with CaP, the exact mechanism by which these Tp53 mutations, in particular gain-of-function (GOF) Tp53 mutations, mediate disease progression remains to be fully elucidated (Tomkova et al., 2008). Tp53-null mice do not develop prostatic intraepithelial neoplasia (PIN) or CaP; however, acceleration and advancement of tumorigenesis is observed in Tp53-null compound models (combining additional oncogenic genetic manipulations), supporting the current dogma that mutations in Tp53 drive late-stage CaP progression (Navone et al., 1993). Somewhat surprisingly, very few genetically engineered mouse models (GEM) that address the contribution of mutant Tp53 to CaP progression exist. Transgenic mice expressing Tp53R270H (equivalent to the human hotspot mutant R273H) under control of the probasin promoter did develop PIN at 1 year of age, but targeted ‘knock in’ of Tp53R270H did not result in any observed prostate pathology (Elgavish et al., 2004; Olive et al., 2004). Owing to the high frequency with which Tp53 is mutated in human CaP, we aimed to develop and characterize GEM with prostate-specific expression of mutant Tp53. Our mouse model challenges the current dogma that mutation in Tp53 is only important in promoting disease progression in late-stage CaP by demonstrating that Tp53 can act as an initiating factor. Here we describe the generation and characterization of the Tp53R270H/+ Nkx3.1-Cre mouse model. This model, which has been bred onto a fully congenic FVB/NJ strain background, conditionally expresses the R270H Tp53 GOF mutation in the prostate epithelium of mice, resulting in the development of both PIN and CaP lesions.