Overexpression Of Pak1 And Pak4 Contributes To Endometrial Carcinogenesis

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction : Endometrial cancer is the most common gynaecological cancer worldwide and its incidence in Asia is rising. It can be classified into two major types: the estrogen dependent type I endometrioid carcinoma that comprises about 80% of endometrial cancers and the type II non-endometroid carcinoma, which is estrogen-independent, including serous carcinoma and clear cell carcinoma. p21-activated kinases (Paks) are major effectors of the small Rho GTPases Rac1 and Cdc42 that play important roles in cell morphology, cytoskeletal reorganization, apoptosis, survival and angiogenesis. This study investigated the expression patterns, clinical significance, functional roles and putative downstream targets of Pak1 and Pak4 in endometrial cancer. Methods and Results : Immunohistochemical study of Pak1, Pak4 and p-Pak4 Ser474 (the activated form) was performed on 10 normal atrophic endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial carcinomas. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus. Significantly higher Pak1, Pak4 and p-Pak4 expression was detected in hyperplastic endometrium and endometrial carcinomas than normal atrophic endometrium. Moreover, endometrioid carcinomas showed significantly higher Pak1 expression than non-endometrioid carcinomas. In endometrial carcinomas, expression of Pak4 was found to be correlated with proliferation markers, MCM7 and Ki67. By quantitative real-time polymerase chain reaction, significantly higher Pak1 and Pak4 mRNA expression was observed in endometrial cancer samples when compared with the corresponding non-tumor counterparts. Up-regulation of Pak1 and Pak4 mRNA and protein expression was also found in cancer cell lines compared with normal endometrial cells. Knockdown of Pak1 by siRNA in RL-95–2, an endometrial cancer cell line with relatively high Pak1 expression, inhibited cell proliferation along with down-regulation of estrogen receptor alpha mRNA and protein expression. Conclusion : This is the first report revealing the expression of Pak1 and Pak4 in normal atrophic, hyperplastic endometrium and endometrial carcinomas, suggesting Pak1 and Pak4 to be useful markers in detection of endometrial carcinoma in postmenopausal women and potential therapeutic targets in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-15. doi:10.1158/1538-7445.AM2011-LB-15