RT Journal Article SR Electronic T1 The Dual ERα Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety. JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.115.100925 DO 10.1124/mol.115.100925 A1 Sang Jun Han A1 Khurshida Begum A1 Charles E Foulds A1 Ross A Hamilton A1 Suzanna Bailey A1 Anna Malovannaya A1 Doug Chan A1 Jun Qin A1 Bert W. O'Malley YR 2015 UL http://molpharm.aspetjournals.org/content/early/2015/10/20/mol.115.100925.abstract AB 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. 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 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 is associated with synergy between the selective recruitment of transcriptional repressors to ERα and FBXO45-mediated degradation of the ERα protein.