Developing improved mouse models of prostate cancer

Genetically modified rodent models provide a platform to dissect the complex and multifactorial mechanisms of prostate cancer initiation and progression. Existing mouse models based on MYC overexpression, including Lo-MYC and Hi-MYC strains, show distinct features of prostatic intraepithelial neoplasia (PIN) and adenocarcinoma that are quite similar to those observed in humans. However, the cancers that emerge in these models rarely progress to metastasis. Evidence is mounting that multiple molecular changes, including loss of tumor suppressor PTEN and MYC overexpression, cooperate to promote human prostate carcinogenesis. To better understand the pathobiology of this disease, we have modeled multiple genetic changes associated with prostate carcinogenesis by combining conditional loss of Pten and concomitant activation of MYC within prostate luminal epithelial cells. A triple transgenic mouse model in which the androgen independent Hoxb13 promoter drives MYC expression concurrent with conditional loss of Pten (Hoxb13-Myc/Hoxb13-Cre/Pten-l- ) was generated. To date, tissues from thirty triply transgenic (Myc+, Cre+, Pten-/-) mice (referred to as BMTs) have been examined for disease progression and by immunohistochemical analyses. By two months of age, BMTs have developed high-grade PIN lesions and have lost expression of the key tumor suppressor Nkx3.1. By four months of age, these mice have developed adenocarcinoma that has metastasized lymph nodes (20/20), liver (13/20), and lung (11/20), mimicking the progression of human prostate cancer. Expression of several key markers including Cytokeratin 18 (CK18), Cytokeratin 8 (CK8), FoxA1, focal AR expression, and loss of p63 in the primary and metastatic tumors provides strong evidence that these tumors are adenocarcinomas of prostate origin. Comparative Genomic Hybridization (CGH) analyses using DNA from primary and metastatic lesions of four different mice were performed. Over 250 DNA copy number (DCN) changes were identified, indicating that genomic instability accompanied disease progression, in parallel with human prostate cancer. This innovative mouse model provides a powerful platform in which the molecular events underlying the progression from PIN through highly penetrant lethal metastatic disease can be systematically analyzed.