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

Han, Sang Jun; Begum, Khurshida; Foulds, Charles E.; Hamilton, Ross A.; Bailey, Suzanna; Malovannaya, Anna; Chan, Doug W.; Qin, Jun; O’Malley, Bert W.

doi:10.1124/mol.115.100925

Cited by 28 publications

(24 citation statements)

References 62 publications

(54 reference statements)

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“…The modest antiarthritic effect of BZA treatment alone, compared with E2 treatment, may be explained by the lower affinity of BZA for ER␣ (23). The ER antagonistic effect of a TSEC in breast and uterus is due to recruitment of transcriptional corepressors as well as direct degradation of the ER␣ protein (24). Thus, we speculate that antiarthritic effects of combined BZA/E2 is primarily mediated by E2, acting via ER␣, and that BZA is not inducing corepressor expression or degrading ER␣ in the cells responsible for arthritis inhibition.…”

Section: Discussionmentioning

confidence: 93%

Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex

et al. 2016

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In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17β-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.

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Section: Discussionmentioning

confidence: 93%

Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex

et al. 2016

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“…On the other hand, FBXO45 has been found to play a role in neural development and tumorigenesis (Peschiaroli et al, 2009, Saiga et al, 2009, Wang and Wei, 2014). To this end, previous studies have shown that FBXO45 is an estrogen-induced gene that contains estrogen receptor-binding sequences (Han et al, 2016, Yoshida, 2005). Further study suggests that Era could be a substrate of FBXO45 (Han, Begum, 2016).…”

Section: Roles Of Fbxo Sub-family In Cell Cyclementioning

confidence: 99%

Ubiquitination-mediated degradation of cell cycle-related proteins by F-box proteins

Zheng

Wang

Wei

2016

The International Journal of Biochemistry & Cell Biology

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F-box proteins, subunits of SKP1-cullin 1-F-box protein (SCF) type of E3 ubiquitin ligase complexes, have been validated to play a crucial role in governing various cellular processes such as cell cycle, cell proliferation, apoptosis, migration, invasion and metastasis. Recently, a wealth of evidence has emerged that F-box proteins is critically involved in tumorigenesis in part through governing the ubiquitination and subsequent degradation of cell cycle proteins, and dysregulation of this process leads to aberrant cell cycle progression and ultimately, tumorigenesis. Therefore, in this review, we describe the critical role of F-box proteins in the timely regulation of cell cycle. Moreover, we discuss how F-box proteins involve in tumorigenesis via targeting cell cycle-related proteins using biochemistry studies, engineered mouse models, and pathological gene alternations. We conclude that inhibitors of F-box proteins could have promising therapeutic potentials in part through controlling of aberrant cell cycle progression for cancer therapies.

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“…This differential recruitment of ER coregulators by estrogens versus SERMs can be attributed, at least in part, to the different ER conformational changes induced by the binding of these ligands (Alio Del Barrio et al, 2017). In addition, TSEC was shown to cause ERα degradation via the ubiquitin proteasome system in the breast and uterus, which was at least in part responsible for the suppression of ERα-mediated transcription (Han et al, 2016). However, this ERα modulation appears to be cell-and tissue-specific since BZA treatment was able to exert an estrogenmimetic action on bone (Palacios et al, 2015) and on the metabolism contributing to beneficial glucidic and lipidic effects (Barrera et al, 2014, Kim et al, 2014.…”

Section: Introductionmentioning

confidence: 99%

The antagonist properties of Bazedoxifene after acute treatment are shifted to stimulatory action after chronic exposure in the liver but not in the uterus

Buscato

Fontaine

Fabre

et al. 2018

Molecular and Cellular Endocrinology

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A promising alternative to conventional hormone therapy for postmenopausal symptoms is treatment combining Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), and conjugated equine estrogen (CE). This combination is also known as a tissue-selective estrogen complex (TSEC). Understanding the tissue-specific actions of SERMs and the TSEC remains a major challenge to try to predict their clinical effects. The aim of this study was to compare acute versus chronic treatment with BZA, CE or CE + BZA in two major targets of estrogens, the uterus and the liver. In these two tissues, acute treatment with CE, but not with BZA, induced similar gene expression change than the most important endogenous estrogen, 17-β estradiol (E2). Acute induction of gene expression by E2 or by CE was antagonized by the addition of BZA. Concomitantly, BZA alone or in combination with E2 or CE induced a partial degradation of ERα protein after acute exposure. In uterus, chronic treatment of BZA alone had no impact on tissue weight gain or on epithelial cell proliferation, and also antagonized CE-effect in uterus, thereby mimicking the acute effect. By contrast, in the liver, chronic BZA and CE + BZA elicited agonistic transcriptional effects similar to those of CE alone. In addition, at variance to BZA acute effect, no change in ERα protein abundance was observed after chronic treatment in this tissue. These experimental in vivo data highlight a new aspect of the time-dependent tissue-specific action of BZA or TSEC, i.e. they can act acutely as antagonists but become agonists after chronic treatment. This shift was observed in liver tissue, but not in proliferative sex target such as the uterus.

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The Dual Estrogen ReceptorαInhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety

Cited by 28 publications

References 62 publications

Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex

Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex

Ubiquitination-mediated degradation of cell cycle-related proteins by F-box proteins

The antagonist properties of Bazedoxifene after acute treatment are shifted to stimulatory action after chronic exposure in the liver but not in the uterus

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