Dual targeting of estrogen receptor α and estrogen-related receptor α: a novel endocrine therapy for endometrial cancer

OncoTargets and Therapy

关键词: ERα;    ERRα;    SERM;    XCT790;    anti-tumor effect;   

DOI  :  

来源: DOAJ

【 摘 要 】

XiaoDan Mao,1,* Binhua Dong,1,* Min Gao,2 GuanYu Ruan,1 MeiMei Huang,1 Elena Ioana Braicu,3 Jalid Sehouli,3 PengMing Sun11Laboratory of Gynecologic Oncology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, People’s Republic of China; 2Department of Gynecology Oncology, Peking University Cancer Hospital, Beijing 100142, People’s Republic of China; 3Department of Gynecology, Campus Virchow-Klinikum, Charité Universitätmedizin Berlin, Berlin D-13353, GermanyCorrespondence: PengMing SunLaboratory of Gynecologic Oncology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, No. 18 Daoshan Road, Fuzhou 350001, Fujian, People’s Republic of ChinaTel [phone]Fax [phone]Email [e-mail]*These authors contributed equally to this workBackground: Endometrial cancer (EC) is a hormone dependent carcinoma that may involve complex molecular mechanisms. Endocrine therapy by blocking the estrogen and estrogen receptor α (ERα) has been effective in breast cancer, while it is still controversial in EC. Recently, estrogen-related receptor α (ERRα) was proven to be another endocrine therapy target.Methods: The anti-tumor effect of selective estrogen receptor modulators (SERMs) and XCT790 (XCT) used alone or in combination were evaluated in both of ERα-positive (ERα+) and ERα-negative (ERα-) EC cells. ERα and ERRα mRNA were tested by qPCR, while the protein was detected by Western blot. The proliferation was tested by MTS and cell cycle, apoptosis rate were analyzed by flow cytometry.Results: A relatively high dose (10 μM) of tamoxifen (TAM) suppressed the expression of ERα and ERRα in two types of EC cells. However, 10 μM raloxifene (RAL) exhibited no effect on ERα and ERRα, while 10 μM XCT down regulated ERRα specifically, but not ERα in all EC cells. When dual targeting on ERα and ERRα by combining TAM with XCT, the proliferation inhibitory effect and apoptosis reached the strongest in all EC cells (P<0.05). Moreover, the inhibitory effect of proliferation was attributed significantly to the G0/G1 arrest (P<0.05). Interestingly, the apoptosis induced by combining TAM with XCT were obviously higher in ERα+ EC cells than ERα- EC cells (P<0.05).Conclusion: Taken together, the results indicate that dual targeting on ERα and ERRα represents a better anti-tumor effect, which provides a novel endocrine based therapy strategy for EC.Keywords: ERα, ERRα, SERM, XCT790, anti-tumor effect

【 授权许可】

Unknown