Deletion of p21/Cdkn1a confers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model.
Cyclin-dependent kinase inhibitors (CDKIs) p21(Cip1/Waf1) (p21) and p27(Kip1) (p27) play a determining role in cell cycle progression by regulating CDK activity; however, p21 role in prostate cancer (PCa) is controversial. Whereas p21 upregulation by anticancer agents causes cell cycle arrest in various PCa cell lines, elevated p21 levels have been associated with higher Gleason score, poor survival and increased PCa recurrence. These conflicting findings suggest that more studies are needed to examine p21 role in PCa. Herein, employing genetic approach, transgenic mice harboring p21/Cdkn1a homozygous deletion (p21(-/-)) were crossed with the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice to characterize in vivo consequences of p21 deletion on prostate tumorigenesis. Lower urogenital tract weight of p21(-/-)/TRAMP mice was significantly lower than those of p21(+/-)/TRAMP and TRAMP mice. Histopathology further supported these observations, showing less aggressiveness in prostates of p21(-/-)/TRAMP. Furthermore, a significantly higher incidence of low-grade prostatic intraepithelial lesions (PIN) with a concomitant reduction in adenocarcinoma incidence was observed in p21(-/-)/TRAMP mice compared with TRAMP mice. In addition, whereas 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 with TRAMP mice. Together, our data showed that p21 deletion reduces prostate tumorigenesis by slowing-down progression of PIN (pre-malignant) to adenocarcinoma (malignant), suggesting that intact p21 expression is associated with PCa aggressiveness, while its decreased levels may in fact confer protection against prostate tumorigenesis.
['Jain|Anil K|AK|', 'Raina|Komal|K|', 'Agarwal|Rajesh|R|']
D000230:Adenocarcinoma D000818:Animals D063646:Carcinogenesis D050759:Cyclin-Dependent Kinase Inhibitor p21 D004195:Disease Models, Animal D018450:Disease Progression D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D060787:Neoplasm Grading D011471:Prostatic Neoplasms
cell cycle prostate cancer TRAMP p21 knockdown