Tp53 mutations are common in prostate cancer (CaP), occurring with a frequency of ~30% and ~70% in localized and metastatic disease respectively. In vitro studies have determined several common mutations of Tp53 that have specific gain of function properties in addition to loss of function, including the ability to promote castrate resistant growth of CaP cells in some contexts. To date, a lack of suitable mouse models has prohibited investigation of the role played by p53 mutations in mediating CaP progression in vivo. Here we describe the effects of conditional expression of a mutant p53 that is equivalent to the human hotspot R273H into the prostate epithelium of mice. Heterozygous 'p53LSL.R270H/+' (129S4(Trp53tm3Tyj);Nkx3.1cre' (129S(Nkx3-1tm3CreMms) mice with prostate-specific expressionof the p53.R270H mutation (p53R270H/+ Nkx3.1cre mice) bred on to a FVB/N background via speed congenesis to produce strain FVB.129S4(Trp53tm3Tyj/wt);FVB.129S(Nkx3-1tm3CreMms/wt) and littermate genotype negative control mice. These mice had significantly increased incidences of prostatic intraepithelial neoplasia (PIN) lesions that appeared earlier compared to the Nkx3.1 haploinsufficient (Nkx3.1cre het) littermate mice that did not express the Tp53 mutation. PIN lesions in these mice showed consistent progression, and invasive adenocarcinoma that evolved into a high grade, sarcomatoid or epithelial-mesenchymal transition (EMT) phenotype. PIN lesions were similar to those seen in PTEN conditional knockout mice, with evidence of AKT activation concomitant with neoplastic proliferation. Meanwhile, the invasive tumor phenotype was unlike any previously described mouse model of prostatic neoplasia. These data indicate the p53R270H mutation plays a role in CaP initiation. This finding has not previously been reported. Further characterization of this model, particularly in a setting of androgen deprivation, should allow further insights into the mechanisms by which the p53R270H mutation mediates CaP progression.
- Received November 3, 2011.
- Accepted April 3, 2012.
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