Abstract 306: Deletion of p21/Cdkn1a confers protective effect against prostate tumorigenesis in Transgenic Adenocarcinoma of the Mouse Prostate model.

Abstract

Abstract Mutations in tumor suppressor genes and proto-oncogenes, and constitutively active mitogenic signaling are known to cause cell cycle deregulation and uncontrolled proliferation in tumorigenesis. Cyclin dependent kinase inhibitors (CDKIs), p21 and p27, play a determining role in G1-S transition by regulating cyclin dependent kinase (CDK) activity. While lower protein p27 expression is often associated with poor prognosis in PCa, the prognostic significance of p21 in PCa is still controversial. Whereas up regulation of p21 by anticancer agents has been shown to induce growth arrest in several androgen-dependent and -independent PCa cell lines, in many cases, the elevated p21 levels in human PCa tissues have been correlated with higher Gleason score, poor survival and increased recurrence rate of the disease. However, some reports have also associated high p21 levels with metastasis-free survival in PCa patients. Thus, these mixed observations warrant extensive studies to examine the roles of p21 molecule in PCa progression. Accordingly, in the present study, transgenic mice harboring p21/Cdkn1a homozygous deletion (p21-/-) were crossed with the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice so as to characterize the in vivo consequences of p21 deletion on prostate tumor initiation and progression. At 24 weeks of age, necropsy was performed across the groups; the lower urogenital tract (LUT) weight of the p21-/-/TRAMP (male TRAMP mice with homozygous deletion of p21) mice was found to be significantly lower than the LUT weights of both p21+/-/TRAMP (male TRAMP mice with heterozygous deletion of p21) and male TRAMP mice. Detailed histopathological analysis revealed the same trend as gross pathology showing less aggressiveness in prostates of p21-/-/TRAMP. Importantly, there was a marked difference in tumor incidence between TRAMP and p21/TRAMP male mice. A significantly higher incidence of low-grade prostatic intraepithelial lesions with a concomitant reduction in adenocarcinoma incidence was observed in p21-/-/TRAMP mice compared to TRAMP mice. In addition, where TRAMP mice showed the presence of poorly differentiated adenocarcinoma lesions, no such lesions were observed in p21/TRAMP transgenic mice. Specifically, there was a significant reduction in the severity of lesions in both p21-/-/TRAMP and p21+/-/TRAMP mice compared to TRAMP mice; a better protective effect due to homozygous p21 deletion was observed in p21-/-/TRAMP mice. Overall, these results suggest the possibility that intact p21 expression is associated with PCa aggressiveness, while its decreased levels may in fact confer protection against prostate tumorigenesis. Citation Format: Anil Kumar Jain, Komal Raina, Rajesh Agarwal. Deletion of p21/Cdkn1a confers protective effect against prostate tumorigenesis in Transgenic Adenocarcinoma of the Mouse Prostate model. [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 306. doi:10.1158/1538-7445.AM2013-306