The Dual Estrogen Receptor α Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety

• DOI: 10.1124/mol.115.100925
• Publication Date: 2015-10-21T02:27:41Z
• Authors: Sang Jun Han; Khurshida Begum; Charles E. Foulds; Ross A. Hamilton; Suzanna Bailey; Anna Malovannaya; Doug Chan; Jun Qin; Bert W. O’Malley
• Keywords: Selective Estrogen Receptor Modulators; 0303 health sciences; Estrogens, Conjugated (USP); Endometriosis; Estrogen Receptor alpha; Breast Neoplasms; Estrogens; 3. Good health; Mice, Inbred C57BL; Endometrium; Mice; 03 medical and health sciences; MCF-7 Cells; Animals; Humans; Female; Breast; HeLa Cells

The conjugated estrogen /: bazedoxifene tissue-selective estrogen complex (TSEC) is designed to minimize the undesirable effects of estrogen in the uterus and breast tissues and to allow the beneficial effects of estrogen in other estrogen-target tissues, such as the bone and brain. However, the molecular mechanism underlying endometrial and breast safety during TSEC use is not fully understood. Estrogen receptor α (ERα)-estrogen response element (ERE)-DNA pull-down assays using HeLa nuclear extracts followed by mass spectrometry-immunoblotting analyses revealed that, upon TSEC treatment, ERα interacted with transcriptional repressors rather than coactivators. Therefore, the TSEC-mediated recruitment of transcriptional repressors suppresses ERα-mediated transcription in the breast and uterus. In addition, TSEC treatment also degraded ERα protein in uterine tissue and breast cancer cells, but not in bone cells. Interestingly, ERα-ERE-DNA pull-down assays also revealed that, upon TSEC treatment, ERα interacted with the F-box protein 45 (FBXO45) E3 ubiquitin ligase. The loss-of- and gain-of-FBXO45 function analyses indicated that FBXO45 is involved in TSEC-mediated degradation of the ERα protein in endometrial and breast cells. In preclinical studies, these synergistic effects of TSEC on ERα inhibition also suppressed the estrogen-dependent progression of endometriosis. Therefore, the endometrial and breast safety effects of TSEC are associated with synergy between the selective recruitment of transcriptional repressors to ERα and FBXO45-mediated degradation of the ERα protein.