Abstract 388: EGR1 is a mediator of TWEAK-Fn14 pathway induced prostate cancer bone metastasis

Abstract

Abstract Patients with advanced or castration-resistant prostate cancer have a high probability of developing bone metastasis. However, the molecular mechanisms driving bone metastasis in prostate cancer remain poorly understood. We have previously demonstrated that Fn14 expression is increased significantly in metastatic lesions from prostate cancer patients. Fn14 is a member of the TNF receptor family, and our in vivo study using DU145/RasB1 cells indicated that the TWEAK-Fn14 pathway promotes prostate cancer bone metastasis via the canonical NFκB pathway. However, the downstream targets of the TWEAK-Fn14 pathway have yet to be characterized in prostate cancer cells. To elucidate the precise mechanism underlying Fn14-promoted metastasis, we analyzed the gene expression profile of highly metastatic DU145/RasB1 and low metastatic DU145/RasB1 Fn14depleted (Fn14KD) cells. Fn14 depletion significantly altered expression of 147 genes, including ECM components, cell adhesives, and cytoskeletal regulators. In addition, DU145/RasB1 and DU145/RasB1 Fn14KD cells responded differently to TWEAK treatment. We found increased expression of early growth response 1, (EGR1), in the TWEAK-treated DU145/RasB1 cells relative to DU145/RasB1 Fn14KD cells. To determine if EGR1 plays a role in prostate cancer metastasis, we depleted EGR1 expression with two shRNAs in highly metastatic DU145/RasB1 cells. Our results show that both EGR1 shRNAs significantly inhibited bone metastasis in vivo. We also found that EGR1 expression was decreased when the NFκB pathways were inhibited by an IκB super repressor in DU145/RasB1 cells. Interestingly, both Fn14 depletion and EGR1 depletion increased TFPI2 expression and inhibited adhesion to fibrin. Fibrin has been shown to facilitate metastatic spread by assisting platelet adhesion to circulating tumor cells. These results suggest one scenario whereby activation of Fn14 signaling may promote prostate cancer bone metastasis through enhancing tumor-platelet interaction via an EGR1-dependent mechanism. Citation Format: Amir H. Ameri, JuanJuan Ivy Yin, Keith Jansen, Simeng Wang, Jessica Snyder, Paul Hynes, Kathleen Kelly. EGR1 is a mediator of TWEAK-Fn14 pathway induced prostate cancer bone metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 388. doi:10.1158/1538-7445.AM2015-388