The Dual Estrogen Receptor α 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 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.

• Authors: Sang Jun Han, Khurshida Begum, Charles E Foulds, Ross A Hamilton, Suzanna Bailey, Anna Malovannaya, Doug Chan, Jun Qin, Bert W O'Malley
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 89 Issue 1 Pg. 14-26 (Jan 2016) ISSN: 1521-0111 [Electronic] United States
• PMID: 26487511 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• Estrogens
• Estrogens, Conjugated (USP)
• Selective Estrogen Receptor Modulators

Topics

• Animals
• Breast (drug effects, metabolism)
• Breast Neoplasms (drug therapy, metabolism)
• Endometriosis (drug therapy, metabolism)
• Endometrium (drug effects, metabolism)
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Estrogens (pharmacology, therapeutic use)
• Estrogens, Conjugated (USP) (pharmacology, therapeutic use)
• Female
• HeLa Cells
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred C57BL
• Selective Estrogen Receptor Modulators (pharmacology, therapeutic use)