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Updated: Sep 25, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
2',3',4'-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a
Candice B Herber1,2, Chaoshen Yuan1,3, Anthony Chang1,4
1Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, 94720-3104, USA.
Background:
Menopausal hormone therapy (MHT) is recommended for only five years to treat vasomotor symptoms and vulvovaginal atrophy because of safety concerns with long-term treatment. We investigated the ability of 2',3',4'-trihydroxychalcone (2',3',4'-THC) to modulate estrogen receptor (ER)-mediated responses in order to find drug candidates that could potentially prevent the adverse effects of long-term MHT treatment.
Methods:
Transfection assays, real time-polymerase chain reaction, and microarrays were used to evaluate the effects of 2',3',4'-THC on gene regulation. Radioligand binding studies were used to determine if 2',3',4'-THC binds to ERα. Cell proliferation was examined in MCF-7 breast cancer cells by using growth curves and flow cytometry. Western blots were used to determine if 2',3',4'-THC alters the E2 activation of the MAPK pathway and degradation of ERα. Chromatin immunoprecipitation was used to measure ERα binding to genes.
Results:
The 2',3',4'-THC/E2 combination produced a synergistic activation with ERα on reporter and endogenous genes in human U2OS osteosarcoma cells. Microarrays identified 824 genes that we termed reprogrammed genes because they were not regulated in U2OS-ERα cells unless they were treated with 2',3',4'-THC and E2 at the same time. 2',3',4'-THC blocked the proliferation of MCF-7 cells by preventing the E2-induced activation of MAPK and c-MYC transcription. The antiproliferative mechanism of 2',3',4'-THC differs from selective estrogen receptor modulators (SERMs) because 2',3',4'-THC did not bind to the E2 binding site in ERα like SERMs.
Conclusion:
Our study suggests that 2',3',4'-THC may represent a new class of ERα modulators that do not act as a direct agonists or antagonists. We consider 2',3',4'-THC to be a reprogramming compound, since it alters the activity of ERα on gene regulation and cell proliferation without competing with E2 for binding to ERα. The addition of a reprogramming drug to estrogens in MHT may offer a new strategy to overcome the adverse proliferative effects of estrogen in MHT by reprogramming ERα as opposed to an antagonist mechanism that involves blocking the binding of estrogen to ERα.
Insights
2
Area of Science:
- Endocrinology and Molecular Biology
- Estrogen Receptor (ER) Signaling Pathways
- Drug Discovery and Development
Background:
- Menopausal Hormone Therapy (MHT) is limited to five years due to safety concerns.
- Long-term MHT risks necessitate alternative strategies for managing menopausal symptoms.
- Estrogen Receptor (ER)-mediated responses are key targets for therapeutic intervention.
Purpose of the Study:
- To investigate 2',3',4'-trihydroxychalcone (2',3',4'-THC) as a novel modulator of ER-mediated responses.
- To identify potential drug candidates for mitigating adverse effects of long-term MHT.
- To explore a new class of ER modulators distinct from traditional SERMs.
Main Methods:
- Gene regulation analysis using transfection assays, real-time PCR, and microarrays.
- Assessment of ERα binding affinity via radioligand binding studies.
- Evaluation of cell proliferation and pathway activation (MAPK) in MCF-7 cells.
- Analysis of ERα degradation and gene binding using Western blots and ChIP assays.
Main Results:
- 2',3',4'-THC synergistically activated ERα on reporter and endogenous genes with E2.
- Microarrays identified 824 'reprogrammed genes' regulated only by the 2',3',4'-THC/E2 combination.
- 2',3',4'-THC inhibited MCF-7 cell proliferation by blocking E2-induced MAPK and c-MYC activation.
- Unlike SERMs, 2',3',4'-THC did not bind to the ERα ligand-binding domain.
Conclusions:
- 2',3',4'-THC represents a novel class of ERα modulators, termed 'reprogramming compounds'.
- This compound alters ERα activity without direct antagonism or agonism at the binding site.
- Reprogramming compounds like 2',3',4'-THC offer a potential new strategy for safer MHT.
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