Pik3ca mutations are frequently observed in endometrial carcinomas. Inappropriate activation of PI3Kα-mediated signaling results in increased AKT-dependent or AKT-independent signaling. The PI3K/AKT signaling pathway plays a critical role in the maintenance of equilibrium between cell survival and apoptosis. In order to investigate the role of Pik3ca in uterine function and tumorigenesis, we generated a mouse model in which Pik3ca gene expression is ablated specifically in the PR-expressing cells (PRcre/+ Pik3caf/f). Ablation of Pik3ca was confirmed by real time PCR, western blot, and immunohistochemical analysis of the uteri. PRcre/+ Pik3caf/f mice were subfertile due to defective uterine development. PRcre/+ Pik3caf/f mice showed significantly decreased uterine weight compared Pik3caf/f mice at 2 months of age. Interestingly, PRcre/+ Pik3caf/f mice exhibited a defect of endometrial gland development. Number of glandular epithelia were significantly decreased in PRcre/+ Pik3caf/f mice compared to control Pik3caf/f mice. The expression of Foxa2, a specific glandular epithelial marker, was significantly decreased in PRcre/+ Pik3caf/f mice and apoptosis was significantly increased in the luminal epithelium of PRcre/+ Pik3caf/f mice. These results indicate that Pik3ca plays a role in female fertility and uterine development.

(This work was supported by NIH U54 HD007495 to J.P.L, Basic Science Research Program (2010-0009047) funded by the MEST, Korea to U-H.H., and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG to J.W.J.)

Citation Format: Heesung Shin, Tae Hoon Kim, Jung-Yoon Yoo, Jean J. Zhao, John P. Lydon, Un-Hwan Ha, Jae-Wook Jeong. The role of Pik3ca in uterine gland morphogenesis and fertility in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 94. doi:10.1158/1538-7445.AM2014-94