Abstract 1086: MYC overexpression combined with Pten loss generates genomic instability and rapid metastasis in a new mouse model of lethal prostate adenocarcinoma.

There is a pressing need for animal models that recapitulate key pathological features of lethal human prostate adenocarcinoma. The availability of these models would facilitate studies to elucidate the molecular events underlying disease progression, and would be invaluable for evaluating new treatment efficacy. Within extant mouse models, metastasis is rare and typically occurs at an advanced age. Using a bacterial artificial chromosome-based transgenic approach, we generated mice in which Hoxb13 regulatory elements drive expression of human MYC (Hoxb13MYC+) or Cre recombinase (Hoxb13Cre+). Hoxb13Cre+ mice were bred to mice carrying floxed Pten (Ptenfl) alleles to generate focal loss of Pten in the prostate epithelium. We then generated mice carrying both the Hoxb13MYC+ and Hoxb13Cre+ transgenes that also harbored two Ptenfl alleles. Phenotypic analyses of Hoxb13MYC+|Hoxb13Cre+| Ptenfl/fl males revealed pervasive low-grade mouse-PIN (mPIN) in all prostate lobes emerging at two weeks of age that became pervasive that progressed to high-grade mPINby four weeks. The lesions bore hallmarks of human PIN including increased nuclear and nucleolar size and dispersed chromatin. Immunostaining revealed MYC and androgen receptor expression and focal Pten loss within the epithelial compartment. mPIN incidence high-gradewas higher in ventral and anterior lobes. By twelve weeks, lesions progressed to cribriform mPIN/intraductal carcinoma was widespread and scattered intraductal carcinoma lesions were observed. At sixteen weeks, in all animals, large frank invasive adenocarcinoma lesions involving multiple prostate lobes were was present as well as, and histological analyses confirmed the presence of invasive poorly differentiated adenocarcinoma. Interestingly, by 16 weeks, metastasis to pelvic and peritoneal lymph nodes occurred with 100% penetrance. In survival analyses, all Hoxb13MYC+|Hoxb13Cre+| Ptenfl/fl mice (N=12) reached criteria for euthanasia within 28 weeks. Liver and lung metastases were observed with high penetrance (>80%). In one case, metastatic spread to a thoracic vertebra was observed, which may represent the first hematogenous metastasis to bone in a mouse prostate cancer model. Copy number analyses using array-based comparative genomic hybridization revealed clonal gene gains and losses in primary prostate cancers and matched metastatic lesions, indicative of genomic instability. The incidence of aggressive cancer and the reproducible chronology of events will enable this model to serve as a robust platform to test strategies to interfere with disease initiation and progression. The lethal phenotype will permit analyses of potentially life extending therapies. In addition, these features will enable studies to dissect the pivotal molecular events that drive the stepwise progression/evolution of this disease. Citation Format: Gretchen K. Hubbard, Laura N. Mutton, May Khalili, Ryan P. McMullin, Jessica Hicks, Daniella Bianchi-Frias, Peter S. Nelson, Srinivasan Yegnasubramanian, Angelo M. De Marzo, Charles J. Bieberich. MYC overexpression combined with Pten loss generates genomic instability and rapid metastasis in a new mouse model of lethal prostate adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1086. doi:10.1158/1538-7445.AM2013-1086