The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic, Sofia; Börjesson, Anna; Farman, Helen H; Sjögren, Klara; Windahl, Sara H; Lagerquist, Marie K; Andersson, Annica; Stubelius, Alexandra; Carlsten, Hans; Gustafsson, Jan Åke; Ohlsson, Claes

doi:10.1073/pnas.1322910111

Cited by 46 publications

(37 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The fact that GPER activation causes vasodilation is consistent with the hypotensive side effects observed in some patients receiving Faslodex® (Vergote and Abram, 2006) . The understanding of fulvestrant action has however been further complicated by the recent finding that this compound may also act as an ERα agonist when the activation function-2 (AF-2) of ERα is mutated (Borjesson et al, 2011; Moverare-Skrtic et al, 2014). Finally, the question as to whether polymorphisms of the GPER gene, which maps to chromosome 7p22, a locus also associated with resistant arterial hypertension in genetic linkage studies in humans (Lafferty et al, 2000; Haas et al, 2009), may be associated with changes in cardiovascular disease risk, is beginning to be addressed in arterial hypertension (Feldman et al, 2013) as is the relationship of GPER polymorphisms to human seminoma risk (Chevalier et al, 2014).…”

Section: Outlook and Potential Clinical Applicationsmentioning

confidence: 99%

Estrogen biology: New insights into GPER function and clinical opportunities

Prossnitz

Barton

2014

Molecular and Cellular Endocrinology

324

267

View full text Add to dashboard Cite

Estrogens play an important role in the regulation of normal physiology, aging and many disease states. Although the nuclear estrogen receptors have classically been described to function as ligand-activated transcription factors mediating genomic effects in hormonally regulated tissues, more recent studies reveal that estrogens also mediate rapid signaling events traditionally associated with G protein-coupled receptors. The G protein-coupled estrogen receptor GPER (formerly GPR30) has now become recognized as a major mediator of estrogen’s rapid cellular effects throughout the body. With the discovery of selective synthetic ligands for GPER, both agonists and antagonists, as well as the use of GPER knockout mice, significant advances have been made in our understanding of GPER function at the cellular, tissue and organismal levels. In many instances, the protective/beneficial effects of estrogen are mimicked by selective GPER agonism and are absent or reduced in GPER knockout mice, suggesting an essential or at least parallel role for GPER in the actions of estrogen. In this review, we will discuss recent advances and our current understanding of the role of GPER and certain drugs such as SERMs and SERDs in physiology and disease. We will also highlight novel opportunities for clinical development towards GPER-targeted therapeutics, for molecular imaging, as well as for theranostic approaches and personalized medicine.

show abstract

Section: Outlook and Potential Clinical Applicationsmentioning

confidence: 99%

Estrogen biology: New insights into GPER function and clinical opportunities

Prossnitz

Barton

2014

Molecular and Cellular Endocrinology

324

267

View full text Add to dashboard Cite

show abstract

“…Recent reports reveal increasing complexity of these mechanisms that imply direct and indirect activities on bone cells. 20 The bone anabolic effect of both RLX and estrogen, through direct action on bone cells was previously confirmed in a concentration-dependent manner, and was blocked by the ER antagonist, ICI 164,384. 21 Emerging evidence has shown that inhibition of osteoclastogenesis is the main mechanism by which estrogen and RLX prevent bone loss, directly by potently suppressing osteoclast differentiation induced by the ligand of receptor activator of NF-rB (RANKL) and macrophage-colony stimulating factor (M-CSF), through the classical ER -and in dosedependent manner.…”

Section: Discussionmentioning

confidence: 87%

“…The favorable endometrial safety profile of RLX/CE TSEC, would be attributed to blocking of the estrogeninduced DNA transcription, through competitive binding of RLX to the ER, 20 that has been essentially attributed to the peculiar orientation and interaction of the critical alkylaminoethoxy RLX side-chain with the amino acid aspartate Figure 6 The vaginal parameters in all studied groups. Data are represented as mean ± SD, of 10 rats in each group.…”

Section: Discussionmentioning

confidence: 99%

New treatment paradigm of combined raloxifene and conjugated estrogen for postmenopausal symptoms in VCD-induced menopausal rats

Emam

Gheit

2017

Alexandria Journal of Medicine

View full text Add to dashboard Cite

Introduction: The decreased ovarian estrogen production that occurs at menopause, results in osteoporosis and climacteric manifestations, and decreases women's quality of life. The hormone replacement therapy (HRT) is the primary treatment options but has been associated with increased oncogenic potential. The tissue selective estrogen complex (TSEC) is a novel therapy, partnering a selective estrogen receptor modulator (SERM) with one or more estrogens. Aim: Our study was done to evaluate the potential relative estrogenic agonist activities of a SERM, raloxifene (RLX), when dosed alone and its antagonist activities when paired with conjugated estrogen (CE), as a TSEC and its potential use for the postmenopausal osteoporosis, vulvar/vaginal atrophy (VVA) in VCD induced menopausal rat model. Material and methods: Female rats were dosed daily with 4-vinylcyclohexene diepoxide (VCD) (80 mg/kg/d, IP) for 15 days to induce ovarian failure, followed by one month free drug. VCD injected rats received 12 weeks of RLX, CE, or combined RLX/CE with 17b-estradiol (E2), vehicle treated groups used as positive and negative controls, respectively. The bone turnover markers (BTM) were measured. The uterotropic activity was assessed by the uterine index and peroxidase assay. Vaginal wet weight (wt.) and glycogen were measured to evaluate the vaginotropic effects. Uterine and vaginal (ER) protein levels were assayed. Results: Our findings showed that the appropriate RLX/CE dose combination exhibits significant bone sparing with minimal vaginal stimulation and neutral uterine effect. Conclusion: We can conclude that appropriate RLX/CE combination could effectively be a promising alternative for the prevention of postmenopausal osteoporosis and VVA with no oncogenic risk.

show abstract

“…The molecular mechanism of AF-1 or AF-2 activation or cooperative regulation of ERα AF-1 by AF-2 is still unresolved (Arao et al, 2015). Although the ERα AF-2 mutations (ERaAF-2° and AF2ER) disrupt E2-mediated physiological responses, antagonistic ligands such as fulvestrant and tamoxifen activate AF-1 mediated physiological functions in these mutant mice (Arao et al, 2012; Arao et al, 2011a; Moverare-Skrtic et al, 2014). AF2ER females present with disrupted metabolic phenotypes similar to ERaAF-2° and αERKO mice.…”

Section: Physiological Role Of Erα Transactivation Domains In Metabolismmentioning

confidence: 99%

Estrogen Hormone Biology

Hamilton

Hewitt

Arao

et al. 2017

Current Topics in Developmental Biology

248

158

View full text Add to dashboard Cite

The hormone estrogen is involved in both female and male reproduction, as well as numerous other biological systems including the neuroendocrine, vascular, skeletal, and immune systems. Therefore, it is also implicated in many different diseases and conditions such as infertility, obesity, osteoporosis, endometriosis, and a variety of cancers. Estrogen works through its two distinct nuclear receptors, Estrogen Receptor alpha (ERα) and Estrogen Receptor beta (ERβ). Various transcriptional regulation mechanisms have been identified as the mode of action for estrogen, mainly the classical mechanism with direct DNA binding but also a non-genomic mode of action and one using tethered or indirect binding. The expression profiles of ERα and ERβ are unique with the primary sites of ERα expression being the uterus and pituitary gland and the main site of ERβ expression being the granulosa cells of the ovary. Mouse models with knockout or mutation of Esr1 and Esr2 have furthered our understanding of the role each individual receptor plays in physiology. From these studies, it is known that the primary roles for ERα are in the uterus and neuroendocrine system, as female mice lacking ERα are infertile due to impaired ovarian and uterine function, whereas female mice lacking ERβ are subfertile due to ovarian defects. The development of effective therapies for estrogen-related diseases has relied on an understanding of the physiological roles and mechanistic functionalities of ERα and ERβ in various human health and disease.

show abstract

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Cited by 46 publications

References 50 publications

Estrogen biology: New insights into GPER function and clinical opportunities

Estrogen biology: New insights into GPER function and clinical opportunities

New treatment paradigm of combined raloxifene and conjugated estrogen for postmenopausal symptoms in VCD-induced menopausal rats

Estrogen Hormone Biology

Contact Info

Product

Resources

About