Abstract 1711: Regulation of hedgehog signaling by the estrogen receptors

Abstract

The likelihood of developing prostate cancer increases with age; hence with the increasing lifespan of Americans the prevalence of prostate cancer is also increasing. Prostate cancer is responsive to endocrine mediators and while estrogen therapy is a well-known classic treatment regiment for prostate cancer, the inhibition of hedgehog signaling has more recently been reported to be important for prostate cancer therapy. Our lab is interested in the role of hedgehog signaling in prostate cancer development and progression. Despite the fact that several nuclear receptor ligands including estrogen, androgen, oxysterols, progesterone, and vitamin d can affect hedgehog signaling, very few nuclear receptors have been shown to directly affect the pathway. While it has been published the Liver X Receptor (LXR) has been shown to negatively regulate hedgehog signaling, we have found that another nuclear receptor class, the Estrogen Receptors, are also able to modulate the hedgehog signaling pathway and may play a regulatory role on hedgehog pathway activity in prostate cancer. We hypothesize that the Estrogen Receptors are involved in mediating hedgehog signaling in prostate cancer, and compounds that bind to the estrogen receptors can modulate hedgehog signaling. Recent work in our lab examining phytoestrogens’ inhibitory effect on the pathway led us to study the roles of the Estrogen Receptors and estrogenic compounds on hedgehog signaling. We have found that 17β-estradiol (E2) can inhibit the hedgehog signaling pathway, monitored by real-time RT-PCR analysis of Gli1 mRNA in the TRAMP-C2 mouse prostate cancer cell line. Surprisingly the ER antagonist ICI 182,780 was also able to inhibit Gli1 mRNA. While the compounds alone do not significantly reduce cell growth, when E2 and ICI 182,780 are added together they significantly inhibit cell growth in the human prostate cancer cell line PC3M. We also have found by western blot analysis that E2 treatments can reduce Gli1 protein concentrations in TRAMP-C2 cells. Similar results were seen in the Shh Light II cell line, a mouse embryonic fibroblast cell line with a stably transfected 8xGliBS-luciferase construct. In summary, our research has shown that estrogenic treatment can reduce hedgehog signaling in prostate cancer models and that the estrogen receptors potentially play a key role in regulating the hedgehog pathway. By understanding how the hedgehog signaling pathway functions in prostate cancer we may be able to generate therapies that include standard hormone and chemotherapies coupled with new hedgehog therapies currently in the pipeline to create new treatments for men afflicted with prostate cancer. Potentially, this work may lead to second generation hedgehog pathway inhibitors that are needed as resistance is developing to the first generation hedgehog pathway inhibitors now in clinical trials. 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 1711.