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.
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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)
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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
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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)
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