Acceleration Of Mammary Tumorigenesis By Pdk1 And Peroxisome Proliferator-Activated Receptor Delta

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The 3-phosphoinositide-dependant kinase-1 (PDK1) is a master regulator of least 23 members of the AGC protein kinase family, including protein kinase B (PKB/Akt). Genetic alterations which activate PI3K/AKT signaling are common in cancer, and elevated expression of PDK1 has been detected in various cancer types, including breast cancer. To assess the effect of PDK1 over-expression in mammary gland function and tumorigenesis, transgenic mice were generated that express PDK1 in the mammary epithelium under the control of the MMTV promoter. PDK1 over-expression resulted in increased pT308Akt and pS9GSK3β and PPARδ expression, but did not affect the phosphorylation of other targets, such as RSK2, S6K and BAD. Transgenic mice exhibited a moderate acceleration of tumor induction by progestin/DMBA in comparison to wild-type mice, and GW501516 treatment accelerated tumorigenesis in both transgenic and wild-type animals. GW501516 promoted the formation of highly keratinized squamous cell carcinomas in both PDK1 transgenic and wild-type mice, and exhibited a profile of elevated pT308Akt and PPARδ expression. Treatment of wild-type mice with PPARδ agonist GW501516 alone increased PDK1 and pT308Akt expression in mammary epithelium. Thus, MMTV-PDK1 mice provide a model in which PDK1 enhances mammary carcinogenesis through activation of Akt and PPARδ to elicit a cooperative effect in promoting tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3263.