Abstract A46: A new transgenic mouse model of prostate cancer that displays rapid progression from prostate intraepithelial neoplasia to invasive carcinoma.

Abstract Understanding the molecular, biochemical, and cellular mechanisms that underpin prostate cancer progression will reveal new opportunities for targeted therapies. Our NCI-supported Program Project on “Signaling and Progression in Prostate Cancer” is a team of basic and clinician scientists that share the overall goal of defining how prostate cancer cells subvert signal transduction pathways during progression to androgen independence. Projects and cores within our program are developing new model systems intended to recapitulate human disease progression. Core B in the program (Transgenic Models and Animal Imaging) has developed a new transgenic mouse model by combining mutant alleles of genes known to have important roles in human prostate cancer. The model is based on the phosphatase and tensin homolog (Pten) tumor suppressor, which is mutated in approximately 30% of primary prostate cancers. Prostate-specific deletion of Pten in mice has been shown by multiple groups to cause prostatic intraepithelial neoplasia (PIN), which slowly progresses to invasive cancer. This suggests that Pten loss allows the initiation of cancer, but that progression is subject to restraint mechanisms. We hypothesized that a restraint mechanism might depend on signaling via the TGFβ pathway, owing to the prominent role that TGFβ plays in growth control. We show that conditional deletion of Pten and Tgfbr2, the type II receptor for TGFβ, in prostate epithelium results in large, poorly differentiated prostate tumors with 100% penetrance by 12 weeks of age. Mice with Pten and Tgfbr2 deletions acquire invasive adenocarcinoma and bladder obstruction and most die by 15 weeks of age. Androgen depletion by castration does not provide a survival benefit for these mice. Pten loss causes an increase in expression of the cyclin-dependent kinase inhibitor p27, which likely restrains progression in this setting. However, when both Pten and Tgfbr2 are deleted, p27 levels are reduced and cyclin D levels increase. Our results suggest that Tgfbr2 is an important tumor suppressor in prostate cancer and that its loss allows rapid progression when combined with loss of the Pten tumor suppressor. Disruption of the TGFβ-mediated restraint provides a rapid, penetrant, and physiologically relevant preclinical model that will be helpful for analyzing restraint- and progression-related gene expression and signal transduction changes in Pten-dependent tumorigenesis. Citation Format: Glen Bjerke, Chun-Song Yang, Henry Frierson, Bryce Paschal, David Wotton. A new transgenic mouse model of prostate cancer that displays rapid progression from prostate intraepithelial neoplasia to invasive carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A46.