Presentation Authors: Wenbin Song, Xi'an, China, People's Republic of, Huiyang Xu*, Karen M. Doersch, Fu-Ju Chou, Rochester, NY, Dalin He, Yule Chen, Xi'an, China, People's Republic of, Iawen Hsu, Chiuan-Ren Yeh, Rochester, NY, Luke Sien-Shih Chang, Lei Li, Xi'an, China, People's Republic of, Edward Messing, Chawnshang Chang, Shuyuan Yeh, Rochester, NY
Introduction: Renal cell carcinoma (RCC) has the third highest mortality rate among all urological tumors, and 20-30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor beta (ERÎ²) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified.
Methods: Methods included the following. (1).RCC tissue samples for immunohistochemical staining (IHC) and RNA analysis. (2) Analysis of the correlation of ERÎ² expression level and RCC overall survival rate. (3) Lentiviral vector construction and virus production. (4) Cell proliferation and colony formation assays. (5) Cell migration and invasion assays. (6) Authotopic renal capsule implantation of RCC cell tumors. (7) PHTPP, ICI182,780 (Faslodex) and tamoxifen therapy effects on in vivo mouse RCC models. (8) IHC and immunofluorescence staining.
Results: In the present study, we found that expression of ERÎ², but not ERÎ±, increases with tumor stage and grade. We also observed that modification of ERÎ² signals using estrogens/anti-estrogens, shRNA knockdown of ERÎ² and ectopic expression of ERÎ² could affect RCC cell proliferation, migration and invasion. TCGA database analysis showed that the increased ERÎ² is associated with a worse survival for RCC patients. Mechanism analysis revealed that ERÎ² can promote RCC cell invasion via increasing transforming growth factor Î²1 (TGF-Î²1)/SMAD3 signals, and interrupting TGF-Î² 1/SMAD3 signals with a TGFÎ² R1 inhibitor can reverse/block ERÎ² -increased RCC cell migration.
Conclusions: ERÎ² can promote RCC cell invasion via up-regulating TGF-Î²1)/SMAD3 signals. Compared to Faslodex and PHTPP, tamoxifen is not an effective anti-estrogen for RCC treatment. Importantly, preclinical analyses using in vivo mouse models of RCC revealed that targeting of this newly identified ERÎ² /TGF-Î²1/SMAD3 pathway with either the FDA-approved anti-estrogen ICI182,780 (Faslodex) or a selective ERÎ² antagonist PHTPP can significantly reduce RCC tumor growth and invasion, which may be suitable as the basis for novel therapies to more effectively suppress metastatic RCC.
Source of Funding: Urology research fund, and the George Whipple Professorship Endowment of UR Medical Center of US, and National Natural Science Foundation of China..