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

Sang Jun Han, Begum K, Khurshida Begum, Charles E. Foulds, Ross A. Hamilton, Hamilton RA, Suzanna Bailey, Bailey S, Anna Malovannaya, Chan D, Doug W. Chan, Doug Chan, Qin J, Jun Qin, O'Malley BW, Bert W. O’Malley, Bert W O'Malley
Molecular pharmacology · 2015 · vol. 89(1) , pp. 14–26 · doi:10.1124/mol.115.100925 · PMID:26487511 · PMC4702103 · W2183215074
article OA: bronze CC0 ⤵ 3 in-corpus citations
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This research investigates the dual inhibitory effects of a Tissue-Selective Estrogen Receptor Alpha (SERA) modulator on both endometrial proliferation and breast cancer cell growth.

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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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Condition tags

endometriosis

MeSH descriptors

Breast Neoplasms Endometriosis Estrogen Receptor alpha Estrogens, Conjugated (USP) Estrogens, Conjugated (USP) Animals Breast Breast Breast Breast Neoplasms Breast Neoplasms Endometriosis Endometriosis Endometrium Endometrium Endometrium Estrogen Receptor alpha Estrogen Receptor alpha Estrogens Estrogens

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