Abstract 5278: Fbxo22 regulates estrogen signaling and suppresses tamoxifen-induced endometrial cancer

Abstract

Abstract Introduction: Selective estrogen receptor modulators (SERMs), such as tamoxifen, function as agonists or antagonists for estrogen receptors (ERs) in a tissue-specific manner. We have discovered that Fbxo22, a F-box subunit of SCF ubiquitin ligase complex is critical for the functional alteration of SERM (Johmura, et al., J Clin Invest, 2018). SCFFbxo22 ubiquitinates and degrades lysine demethylase 4B (KDM4B) complexed with SERM-bound ER, that triggers release of coactivator SRC from ER, thus mediating antagonistic function of SERM. Without Fbxo22, stabilized KDM4B mediates the interaction of SRC with AF1 domain of ER in the presence of SERM, which only abrogates the interaction of SRC with AF2 domain, resulting in agonistic function. Accordingly, tamoxifen failed to prevent the growth of Fbxo22-depleted, ER-positive breast cancers in vitro and in vivo, and a low level of Fbxo22 in tumor tissues predicted a poorer outcome in ER-positive luminal breast cancers. Hence, Fbxo22 is a critical regulator of estrogen signaling in breast cancer. However, whether it is also important for other estrogen-associated cancers is unknown. To clarify the significance of Fbxo22 in other estrogen-associated cancers, we investigated its role in endometrial carcinogenesis. Methods: Fbxo22 expression in 22, 30, 29 and 30 cases of normal human endometrium, endometrial hyperplasia (EH), atypical endometrial hyperplasia (AEH) and endometrial cancer (EC), respectively, were analyzed by immunohistochemistry. In addition, we established endometrial epithelium-specific conditional Fbxo22 knockout (Fbxo22-cKO) mice by developing Fbxo22-floxed mice and mated them with Lactoferrin-iCre mice, and analyzed spontaneous and tamoxifen-induced endometrial neoplasia. Endometrium of the mice in each phase of estrus cycle was also analyzed after PMSG/hCG-induced synchronization. Results: Fbxo22 was expressed only in secretory phase and was absent in proliferative phase of the human endometrial epithelium, and the expression was inversely correlated with proliferative marker Ki-67. The Fbxo22 expression was down regulated as the endometrium progressed to malignancy (H-score: 124±69, 85±51 and 25±35 for EH, AEH and EC, respectively) (P<0.0001). In consistent with the expression in human menstrual cycle, Fbxo22 was also expressed in diestrus, but not in other phases in mice. Interestingly, the estrus cycle was prolonged in Fbxo22-cKO mice with paradoxical morphology of proliferative epithelial cells with secretory stromal cells. Finally, all five cKO mice developed EH or AEH in four months. The phenotype was accelerated by tamoxifen treatment, with all nine mice developed AEH or EC after one- or two-month tamoxifen treatment whereas wild type mice only developed EH. Conclusion: Fbxo22 is an essential regulator of estrogen signaling in endometrium and prevents endometrial carcinogenesis including that induced by tamoxifen. Citation Format: Atsushi Goda, Satoru Meguro, Yoshikazu Johmura, Wenwen Wu, Ichiro Maeda, Yodo Sugishita, Nao Suzuki, Yasuo Miyoshi, Junki Koike, Makoto Nakanishi, Tomohiko Ohta. Fbxo22 regulates estrogen signaling and suppresses tamoxifen-induced endometrial cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5278.