Abstract 1385: PPARδ promotes mammary tumorigenesis through mTOR activation.

Abstract Background: Peroxisome proliferator-activated receptorδ (PPARδ) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation and proliferation. One or more of these processes are potential risk factors for the ability of PPARδ agonists to promote tumorigenesis in the mammary gland. In the present study, we describe a new transgenic mouse model in which activation of PPARδ by endogenous or synthetic ligands results in mammary neoplasia. Methods: Transgenic mice were generated in which expression of PPARδ was directed to the mammary gland under the control of the MMTV long terminal repeat. Results: Multiparous MMTV-PPARδ mice presented with infiltrating ductal carcinomas after a latency of 12 months. When transgenic animals were maintained on a diet supplemented with the PPARδ ligand GW501516, rapid progression to ductal and alveolar hyperplasia, dysplasia and ductal carcinoma in situ occurred within three months, and multifocal ductal carcinomas occurred after 5 months. Histopathological changes occurred in concert with a marked increase in phosphatidylcholine (PC) and lysoPC levels. Gene array profiling revealed an inflammatory, invasive, metabolic and proliferative signature denoted by enhanced expression of Saa1/2, S100a8, Klk6/7, Acsl4 and Plac1, and increased mTOR signaling. Treatment with the mTOR inhibitor, everolimus, dramatically reversed many of the histopathological and gene expression abnormalities. Conclusion: MMTV-PPARδ mice demonstrate a direct role for PPARδ in breast tumorigenesis that is linked to several previously unknown signaling processes. These findings suggest a rationale for new therapeutic approaches to prevent and treat this disease. Supported by 1N01CN43302-WA19 and 1P30CA51008 1st Choice Category: TB1 Cell Culture and Animal Models of Cancer Citation Format: Robert I. Glazer, Hongyan Yuan, Geeta Upadhyay, Yuzhi Yin, Levy Kopelovich. PPARδ promotes mammary tumorigenesis through mTOR activation. [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 1385. doi:10.1158/1538-7445.AM2013-1385