Identification of coregulators influenced by estrogen receptor subtype specific binding of the ER antagonists 4-hydroxytamoxifen and fulvestrant

Evers, Nynke M.; Wang, Si; Berg, J.H.J. van den; Melchers, Diana; Haan, L.H.J. de; Ederveen, A. G. H.; Groten, J.P.; Rietjens, Ivonne M. C. M.

doi:10.1016/j.cbi.2014.06.019

Cited by 8 publications

(5 citation statements)

References 42 publications

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“…The modulation of interactions by DHT was similar, but clearly distinct from the one recorded for the ER stimulated with estradiol (45). As expected, we observed strong interactions of the agonistbound AR with the coactivator peptides that contain FxxLF motifs.…”

Section: N/c Interactions and Binding To Coregulator Peptidessupporting

confidence: 80%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.

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Section: N/c Interactions and Binding To Coregulator Peptidessupporting

confidence: 80%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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“…As a result, a certain phytoestrogen may have different effects in, for example, the uterus, in which ERα is the major isoform (Pearce and Jordan, ), than in the prostate, in which ERβ is dominant (Enmark et al , ; Pearce and Jordan, ). These tissue‐specific effects may also result from differences in coactivators and corepressors activated upon activation of the two ERs in different tissues and/or the possible crosstalk of the ERs with other nuclear receptors (Wilson et al , ; Chang et al , ; Vanden Berghe and Haegeman, ; Evers et al , ; Evers et al , ). Furthermore, the actual mode of action of a phytoestrogen, either as an agonist or an antagonist, may also depend on the level of endogenous estrogens present (Barnes et al , ).…”

Section: Introductionmentioning

confidence: 99%

The potential health effects of dietary phytoestrogens

Rietjens

Louisse

Beekmann

2016

British J Pharmacology

410

246

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Phytoestrogens are plant‐derived dietary compounds with structural similarity to 17‐β‐oestradiol (E2), the primary female sex hormone. This structural similarity to E2 enables phytoestrogens to cause (anti)oestrogenic effects by binding to the oestrogen receptors. The aim of the present review is to present a state‐of‐the‐art overview of the potential health effects of dietary phytoestrogens. Various beneficial health effects have been ascribed to phytoestrogens, such as a lowered risk of menopausal symptoms like hot flushes and osteoporosis, lowered risks of cardiovascular disease, obesity, metabolic syndrome and type 2 diabetes, brain function disorders, breast cancer, prostate cancer, bowel cancer and other cancers. In contrast to these beneficial health claims, the (anti)oestrogenic properties of phytoestrogens have also raised concerns since they might act as endocrine disruptors, indicating a potential to cause adverse health effects. The literature overview presented in this paper illustrates that several potential health benefits of phytoestrogens have been reported but that, given the data on potential adverse health effects, the current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible health risks. Furthermore, the data currently available are not sufficient to support a more refined (semi) quantitative risk–benefit analysis. This implies that a definite conclusion on possible beneficial health effects of phytoestrogens cannot be made.Linked ArticlesThis article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc

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“…Its mortality rate has fallen with earlier diagnosis, and improvements in medical treatments, including surgery, chemotherapy, radiotherapy and anti-hormonal treatment. By blocking estrogen receptors (ER), the proliferation and metastatic potential of early stage breast cancers can be inhibited by aromatase inhibitors and selective ER modulators, such as Arimidex, Aromasin, Tamoxifen and Faslodex [1]. The reduced production of estrogen as well as competitive drug binding with ERα (estrogen receptor α) prevents ER−estrogen complexes from forming and translocating to the nuclei to trigger the transcription of growth-promoting genes.…”

Section: Introductionmentioning

confidence: 99%

Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2

et al. 2015

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Accumulating evidence suggests that ubiquitin E3 ligases are involved in cancer development as their mutations correlate with genomic instability and genetic susceptibility to cancer. Despite significant findings of cancer-driving mutations in the BRCA1 gene, estrogen receptor (ER)-positive breast cancers progress upon treatment with DNA damaging-cytotoxic therapies. In order to understand the underlying mechanism by which ER-positive breast cancer cells develop resistance to DNA damaging agents, we employed an estrogen receptor agonist, Erb-041, to increase the activity of ERβ and negatively regulate the expression and function of the estrogen receptor α (ERα) in MCF-7 breast cancer cells. Upon Erb-041-mediated ERα down-regulation, the transcription of an ERα downstream effector, BCA2 (Breast Cancer Associated gene 2), correspondingly decreased. The ubiquitination of chromatin-bound BCA2 was induced by ultraviolet C (UVC) irradiation but suppressed by Erb-041 pretreatment, resulting in a blunted DNA damage response. Upon BCA2 silencing, DNA double-stranded breaks increased with Rad51 OPEN ACCESSBiomedicines 2015, 3 183 up-regulation and ataxia telangiectasia mutated (ATM) activation. Mechanistically, UV-induced BCA2 ubiquitination and chromatin binding were found to promote DNA damage response and repair via the interaction of BCA2 with ATM, γH2AX and Rad51. Taken together, this study suggests that Erb-041 potentiates BCA2 dissociation from chromatin and co-localization with Rad51, resulting in inhibition of homologous recombination repair.

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Identification of coregulators influenced by estrogen receptor subtype specific binding of the ER antagonists 4-hydroxytamoxifen and fulvestrant

Cited by 8 publications

References 42 publications

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

The potential health effects of dietary phytoestrogens

Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2

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