Abstract 1110: Estrogen receptor β signaling induced radio-resistance in bladder cancer

Abstract Introduction and Objective: Although radiotherapy (RT) combined with chemotherapy shows comparable outcomes to surgery, women tend to have higher mortality from bladder cancer (BC) compared to men. Emerging evidence indicated the involvement of estrogen receptorβ (ERβ) signaling in BC progression and the association of ER signaling with DNA repair pathways which are involved in radio-resistance. Therefore, we evaluated the association between ERβ signaling and the sensitivity to BC cells. Methods: We compared the inhibitory effect of RT on BC cell viability between ERβ positive 5637 and T24 expressing control short-heparin RNA (shRNA) and ERβ negative (5637 and T24 expressing ERβ-shRNA) cells. Moreover, we compared DNA double-strand breaks (DSB) via γ-H2AX foci formation, as well as the expression levels of DNA repair genes, in these cells after RT. Finally, in a mouse xenograft model, we evaluated it on the growth of ERβ positive tumor treated with radiation combined with mock or tamoxifen treatment. Results: In vitro experiment showed that ionizing radiation reduced the numbers of viable cells in ERβ negative cells more significantly than those in ERβ positive cells. Moreover, tamoxifen treatment reduced the numbers of viable cells more than mock treatment in ERβ positive cells, while tamoxifen didn’t show significant effects in ERβ negative cells. The down-regulation of ERβ resulted in a delay in DSB repair 4-24 hours after RT. We then established radio-resistant cells and confirmed considerable elevation of the expression of ERβ as well as DNA repair genes including RAD51 and RAD54. Estradiol treatment induced the expression of these genes and tamoxifen abolished these effects. Finally, in vivo experiment showed that tamoxifen enhanced the cytotoxic effects of RT in xenograft bearing mice. Conclusions: These results indicated that ERβ signaling inversely correlated with sensitivity to RT in BC. Thus, ERβ inhibition have a potential of enhancing the cytotoxic effects of radiation, especially in ERβ positive BC cells. Citation Format: Hiroki Ide, Tetsushi Murakami, Eiji Kashiwagi, Sotaro Kitaoka, Akari Komatsuda, Chugo Nishimura, Shinsuke Funakoshi, Mototsugu Oya, Hiroshi Miyamoto. Estrogen receptor β signaling induced radio-resistance in bladder cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1110.