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Updated: Jun 3, 2026
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Withaferin a suppresses estrogen receptor-α expression in human breast cancer cells
Eun-Ryeong Hahm1, Joomin Lee, Yi Huang
1Department of Pharmacology & Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Abstract:
We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of MCF-7 and MDA-MB-231 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo by causing apoptosis. However, the mechanism of WA-induced apoptosis is not fully understood. The present study was designed to systematically determine the role of tumor suppressor p53 and estrogen receptor-α (ER-α) in proapoptotic response to WA using MCF-7, T47D, and ER-α overexpressing MDA-MB-231 cells as a model. WA treatment resulted in induction as well as increased S15 phosphorylation of p53 in MCF-7 cells, but RNA interference of this tumor suppressor conferred modest protection at best against WA-induced apoptosis. WA-mediated growth inhibition and apoptosis induction in MCF-7 cells were significantly attenuated in the presence of 17β-estradiol (E2). Exposure of MCF-7 cells to WA resulted in a marked decrease in protein levels of ER-α (but not ER-β) and ER-α regulated gene product pS2, and this effect was markedly attenuated in the presence of E2. WA-mediated down-regulation of ER-α protein expression correlated with a decrease in its nuclear level, suppression of its mRNA level, and inhibition of E2-dependent activation of ERE2e1b-luciferase reporter gene. Ectopic expression of ER-α in the MDA-MB-231 cell line conferred partial but statistically significant protection against WA-mediated apoptosis, but not G2/M phase cell cycle arrest. Collectively, these results indicate that WA functions as an anti-estrogen, and the proapoptotic effect of this promising natural product is partially attenuated by p53 knockdown and E2-ER-α.
Insights
Withaferin A (WA), a natural compound, induces breast cancer cell death partly by acting as an anti-estrogen. Its cancer-fighting effects are partially reduced by p53 and estrogen receptor-alpha (ER-α).
Area of Science:
- * Pharmacology
- * Molecular Biology
- * Cancer Research
Background:
- * Withaferin A (WA), derived from *Withania somnifera*, is a potential anticancer agent that induces apoptosis in breast cancer cells.
- * The precise mechanisms underlying WA-induced apoptosis, particularly the roles of tumor suppressor p53 and estrogen receptor-alpha (ER-α), remain incompletely understood.
- * Understanding these pathways is crucial for developing targeted cancer therapies.
Purpose of the Study:
- * To elucidate the involvement of p53 and ER-α in the proapoptotic effects of WA on human breast cancer cells.
- * To investigate whether WA exhibits anti-estrogenic properties.
- * To assess the impact of 17β-estradiol (E2) and ER-α expression on WA's efficacy.
Main Methods:
- * Utilized human breast cancer cell lines (MCF-7, T47D) and ER-α overexpressing MDA-MB-231 cells.
- * Employed RNA interference to assess the role of p53.
- * Measured apoptosis, cell cycle arrest, protein/mRNA levels, and reporter gene activity.
- * Investigated the effects of WA with and without E2 treatment.
Main Results:
- * WA induced p53 phosphorylation in MCF-7 cells, but p53 knockdown only partially protected against apoptosis.
- * WA-induced apoptosis and growth inhibition were attenuated by E2, suggesting anti-estrogenic activity.
- * WA decreased ER-α and pS2 protein levels, suppressed ER-α mRNA, and inhibited E2-dependent reporter gene activity.
- * Ectopic ER-α expression in MDA-MB-231 cells offered partial protection against WA-induced apoptosis.
Conclusions:
- * Withaferin A exhibits anti-estrogenic properties, contributing to its anticancer effects.
- * The proapoptotic impact of WA is partially mediated by ER-α and influenced by p53.
- * These findings highlight the complex interplay between WA, ER-α, and p53 in breast cancer, offering potential therapeutic insights.
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