estrogen receptor activity
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2021 ◽  
Author(s):  
Andrew Conery ◽  
Archana Bommi-Reddy ◽  
Sungmi Park-Chouinard ◽  
David N. Mayhew ◽  
Esteban Terzo ◽  
...  

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance.  Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself.  In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC.  Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER.  CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1.   These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.


Author(s):  
Camila Calfío ◽  
Francisca Donoso ◽  
J. Pablo Huidobro‐Toro

Background The vascular pharmacodynamics of anthocyanins is only partially understood. To examine whether the anthocyanin‐induced vasorelaxation is related to membrane estrogen receptor activity, the role of ERα or GPER antagonism was ascertained on anthocyanins or 17‐β estradiol‐(E2) induced vasodilatations and NO production. Methods and Results The rat arterial mesenteric bed was perfused with either anthocyanins or corresponding 3‐O‐glycosides, or E2, to examine rapid concentration‐dependent vasorelaxations. The luminally accessible fraction of NO in mesenteric perfusates before and after anthocyanins or E2 administration was quantified. Likewise, NO‐DAF signal detected NO production in primary endothelial cells cultures incubated with anthocyanins or E2 in the absence and presence of ERα (ICI 182,780) or GPER (G‐36) selective antagonists. Anthocyanins or corresponding glycosides elicited, within minutes, vasodilation with nanomolar potencies; half maximal anthocyanin response reached 50% to 60% efficacy, in contrast to acetylcholine. The vasorelaxation is of rapid onset and exclusively endothelium‐dependent; NOS inhibition annulled the vasorelaxation. The delphinidin vascular response was not modified by 100 nmol/L atropine but significantly attenuated by joint application of ICI plus G‐36 (52±4.6 versus 8.5±1.5%), revealing the role of membrane estrogen receptors. Moreover, the anthocyanin or E2‐induced NO production was antagonized up to 70% by these antagonists. NO‐DAF signal elicited by anthocyanins was annulled by NOS inhibition or by ICI plus G‐36 addition. Conclusions The biomedical effect of anthocyanins or 3‐O‐glycosylates derivatives contained in naturally purple‐colored foods or berries is due to increased NO production, and not to the phytochemical's antioxidant potential, highlighting the nutraceutical role of natural products in cardiovascular diseases.


2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Johan Lundqvist ◽  
Kenneth M. Persson ◽  
Agneta Oskarsson

Abstract Background Contamination of drinking water by hazardous chemicals can be associated with human health risks. Recent studies using effect-based in vitro methods have demonstrated that a large part of the observed toxic effects are caused by unknown chemicals. In this study, we have used a panel of effect-based methods to study the presence of chemical contaminants in a unique material; glass-bottled Swedish tap water collected during the 1990s. These water samples were compared to drinking water from the same source waters and drinking water facilities, yet collected about 25 years later, in 2020. Results Samples were concentrated by solid phase extraction and evaluated for the following activities; estrogen receptor activity, androgen receptor activity, antiandrogenic activity, aryl hydrocarbon receptor activity, and oxidative stress response. We observed aryl hydrocarbon receptor activities in almost all studied samples and estrogen receptor activity in three out of ten studied samples. No activities were observed for androgen receptor activity, antiandrogenic activity or oxidative stress response. In general, observed activities were more frequent and higher in the water samples collected during the 1990s as compared to the corresponding samples collected in 2020. Conclusions This study demonstrates that it is possible to conduct an effect-based evaluation of the presence of hazardous chemicals in drinking water, with as small starting volume as 330 mL, by using miniaturized bioassays. Further, by comparing the glass-bottled water samples with newly collected water samples from the same drinking water treatment facilities, our results indicate that the presence of aryl hydrocarbon receptor and estrogen receptor activating compounds in the drinking water has decreased over the approximately quarter of a century that is separating the two sampling occasions. This difference could be due to improved raw water quality and/or improved treatment efficiency in the treatment plants.


Author(s):  
Yahyea Baktiar Laskar ◽  
Monjur Ahmed Laskar ◽  
Pranab Behari Mazumder ◽  
Anupam Das Talukdar

The estrogen hormone receptor (ER) mediated gene expression mainly regulate the development and physiology of primary and secondary reproductive system alongside bone-forming, metabolism and behaviour. Over-expressed ER is associated with several pathological conditions and play a key role in breast cancer occurrence, progression and metastasis. Hibiscus sabdariffa L. or roselle is a rich source of naturally occurring polyphenolic compounds including anthocyanins and reportedly have strong estrogenic activity. To validate these findings, we have investigated the estrogen receptor binding affinity and safety of some previously recorded polyphenols using a suite of computational methods. Our investigation showed the estrogen-receptor binding potential of Pelargonidin, Delphinidin, Cyanidin, and Hibiscetin are more efficient than popular breast cancer drugs, Tamoxifen and Raloxifene, with favourable toxicological parameters and low half maximal inhibitory concentration. This is the first report to investigate the phytochemical basis of estrogenic activity of Hibiscus sabdariffa L.


Endocrinology ◽  
2020 ◽  
Vol 162 (2) ◽  
Author(s):  
Anca M Farcas ◽  
Sankari Nagarajan ◽  
Sabina Cosulich ◽  
Jason S Carroll

Abstract The largest subtype of breast cancer is characterized by the expression and activity of the estrogen receptor alpha (ERalpha/ER). Although several effective therapies have significantly improved survival, the adaptability of cancer cells means that patients frequently stop responding or develop resistance to endocrine treatment. ER does not function in isolation and multiple associating factors have been reported to play a role in regulating the estrogen-driven transcriptional program. This review focuses on the dynamic interplay between some of these factors which co-occupy ER-bound regulatory elements, their contribution to estrogen signaling, and their possible therapeutic applications. Furthermore, the review illustrates how some ER association partners can influence and reprogram the genomic distribution of the estrogen receptor. As this dynamic ER activity enables cancer cell adaptability and impacts the clinical outcome, defining how this plasticity is determined is fundamental to our understanding of the mechanisms of disease progression.


2020 ◽  
Vol 80 (11) ◽  
pp. 2311-2324
Author(s):  
Maria Teresa Majorini ◽  
Valeria Cancila ◽  
Alice Rigoni ◽  
Laura Botti ◽  
Matteo Dugo ◽  
...  

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