Evidence for an alternate molecular progression in prostate cancer

Abstract

SUMMARYTp53 mutations are common in human 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 castration-resistant (CR) growth of CaP cells in some contexts. To date, a lack of suitable mouse models has prohibited investigation of the role played by Tp53 mutations in mediating CaP progression in vivo. Here, we describe the effects of conditional expression of a mutant Tp53 (Tp53R270H; equivalent to the human hotspot mutant R273H) in the prostate epithelium of mice. Heterozygous “Tp53LSL-R270H/+” [129S4(Trp53tm3Tyj)] and “Nkx3.1-Cre” [129S(Nkx3-1tm3(cre)Mms)] mice with prostate-specific expression of the Tp53R270H mutation (p53R270H/+ Nkx3.1-Cre mice) were bred onto an FVB/N background via speed congenesis to produce strain FVB.129S4(Trp53tm3Tyj/wt); FVB.129S(Nkx3-1tm3(cre)Mms/wt) and littermate genotype negative control mice. These mutant mice had significantly increased incidences of prostatic intraepithelial neoplasia (PIN) lesions, and these appeared earlier, compared with the Nkx3.1 haploinsufficient (Nkx3.1-Cre het) littermate mice, which did not express the Tp53 mutation. PIN lesions in these mice showed consistent progression and some developed into invasive adenocarcinoma with 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. However, the invasive tumor phenotype is rarely seen in previously described mouse models of prostatic neoplasia. These data indicate that the Tp53R270H 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 insight into the mechanisms by which the Tp53R270H mutation mediates CaP progression.

ERG Activates the YAP1 Transcriptional Program and Induces the Development of Age-Related Prostate Tumors

“…While sarcomatoid carcinoma is rarely seen in human prostate cancer, these tumors have epithelial origin (Rodrigues et al, 2014). Further, mouse prostate epithelial cells readily undergo EMT and present with sarcomatoid carcinomas, which is seen in mice with deletions of Tp53 , or the activation of K-Ras or COUP-TFII in prostate epithelium (Martin et al, 2011; Mulholland et al, 2012; Qin et al, 2013; Vinall et al, 2012). …”

Mouse models of prostate cancer: picking the best model for the question

“…Additionally, many aggressive GEM models progress to sarcomatoid carcinoma tumors[10], suggesting an inherent difference between human and mouse PCa progression. Some publications have referred to these tumors as adenocarcinomas which have undergone epithelial to mesenchymal transition (EMT)[27-30]. …”

“…Meanwhile, Vinall et al showed that heterozygous knock-in of a common tumor associated p53 mutation (R270H) was sufficient to generate HGmPIN and these sometimes progressed to non-NE sarcomatoid carcinomas. The authors proposed that the mutant p53 was both dominant negative and also might have a gain of function[30]. In human PCa, loss of Rb is believed to occur early in 60% of patients[69], while the loss of p53 by mutation or deletion occurs in 20-40% of more advanced and metastatic disease[70,71].…”

Molecular landscape of prostate cancer: Implications for current clinical trials

“…The tumour suppressor p53 plays a key role in maintaining genomic stability and preventing tumourigenesis [59]. A previous study demonstrated that the TP53 R270H mutation was sufficient to induce prostate cancer in mice [60]. Mutation or deletion of TP53 was associated with increased risk of recurrence [61].…”