Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.
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In Silico Elucidation of the Plausible Inhibitory Potential of Withaferin A of Withania Somnifera Medicinal Herb Against Breast Cancer Targeting Estrogen Receptor
Background: Estrogen Receptors (ER) are members of the nuclear intracellular receptorsfamily. ER once activated by estrogen, it binds to DNA via translocating into the nucleus and regulatesthe activity of various genes. Withaferin A (WA) - an active compound of a medicinal plant Withaniasomnifera was reported to be a very effective anti-cancer agent and some of the recent studies hasdemonstrated that WA is capable of arresting the development of breast cancer via targeting estrogenreceptor. Objective: The present study is aimed at understanding the molecular level interactions of ER and Tamoxifenin comparison to Withaferin A using In-silico approaches with emphasis on Withaferin Abinding capability with ER in presence of point mutations which are causing de novo drug resistance toexisting drugs like Tamoxifen. Methods: Molecular modeling and docking studies were performed for the Tamoxifen and WithaferinA with the Estrogen receptor. Molecular docking simulations of estrogen receptor in complex withTamoxifen and Withaferin A were also performed. Results: Amino acid residues, Glu353, Arg394 and Leu387 was observed as crucial for binding andstabilizing the protein-ligand complex in case of Tamoxifen and Withaferin-A. The potential ofWithaferin A to overcome the drug resistance caused by the mutations in estrogen receptor to the existingdrugs such as Tamoxifen was demonstrated. Conclusion: In-silico analysis has elucidated the binding mode and molecular level interactions whichare expected to be of great help in further optimizing Withaferin A or design / discovery of futurebreast cancer inhibitors targeting estrogen receptor.
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- Award ID(s):
- 2019745
- PAR ID:
- 10235060
- Date Published:
- Journal Name:
- Current Pharmaceutical Biotechnology
- Volume:
- 21
- Issue:
- 9
- ISSN:
- 1389-2010
- Page Range / eLocation ID:
- 842 to 851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.2174/1389201021666200129121843
