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

ABSTRACT: 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 ? (ER?)-estrogen response element (ERE)-DNA pull-down assays using HeLa nuclear extracts followed by mass spectrometry-immunoblotting analyses revealed that, upon TSEC treatment, ER? interacted with transcriptional repressors rather than coactivators. Therefore, the TSEC-mediated recruitment of transcriptional repressors suppresses ER?-mediated transcription in the breast and uterus. In addition, TSEC treatment also degraded ER? protein in uterine tissue and breast cancer cells, but not in bone cells. Interestingly, ER?-ERE-DNA pull-down assays also revealed that, upon TSEC treatment, ER? 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 ER? protein in endometrial and breast cells. In preclinical studies, these synergistic effects of TSEC on ER? 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 ER? and FBXO45-mediated degradation of the ER? protein.

SUBMITTER: Han SJ 

PROVIDER: S-EPMC4702103 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature