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Updated: Sep 1, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer
Abigail Schoeller1, Keshav Karki1, Arul Jayaraman2
1Department of Veterinary Physiology and Pharmacology, Texas A&M University College Station, TX 77843, USA.
Abstract:
Early stage estrogen receptor α (ERα, ESR1)-positive breast cancer patients can develop more aggressive endocrine-resistant tumors that express constitutively active mutant forms of ERα including ERα-Y537S and ERα-D538G. These patients are treated with selective ER down regulators (SERDs) such as the ERα antagonist fulvestrant. Previous studies show that histone deacetylase (HDAC) inhibitors downregulate ERα and since some dietary derived short chain fatty acids (butyrate, propionate and acetate) exhibit HDAC inhibitory activity we investigated their effects as SERDs in MCF-7 and T47D cells expressing wild-type and mutant ERα-D538G and ERα-Y537S. The SCFAs exhibited SERD-like activity in both cell lines expressing wild-type and mutant ERα. The results for propionate and butyrate correlated with parallel induction of histone acetylation and this was also observed for the HDAC inhibitors Panobinostat, Vorinostat and Entinostat which also downregulated wild-type and mutant ERα and induced histone acetylation. Although acetate induced ERα degradation the mechanisms may be independent of the HDAC inhibitory activity of this compound. These results suggest that high fibre diets that induce formation of SCFAs may have some clinical efficacy for treating ER-positive endocrine resistant breast cancer patients and this is currently being investigated.
Insights
Dietary short-chain fatty acids (SCFAs) show promise as selective estrogen receptor downregulators (SERDs) for endocrine-resistant breast cancer. These compounds, like butyrate and propionate, effectively target both wild-type and mutant estrogen receptor alpha (ERα).
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Estrogen receptor alpha (ERα)-positive breast cancer can become endocrine-resistant, often due to constitutively active ERα mutations (e.g., Y537S, D538G).
- Selective estrogen receptor downregulators (SERDs) like fulvestrant are used, but resistance remains a challenge.
Purpose of the Study:
- To investigate the potential of dietary short-chain fatty acids (SCFAs) as novel SERDs.
- To evaluate SCFA efficacy against wild-type and mutant ERα in breast cancer cells.
Main Methods:
- Utilized MCF-7 and T47D breast cancer cell lines expressing wild-type, ERα-Y537S, and ERα-D538G.
- Assessed the effects of SCFAs (butyrate, propionate, acetate) and HDAC inhibitors (Panobinostat, Vorinostat, Entinostat) on ERα levels and histone acetylation.
Main Results:
- SCFAs demonstrated SERD-like activity against both wild-type and mutant ERα.
- Propionate and butyrate induced histone acetylation, correlating with ERα downregulation.
- Acetate also induced ERα degradation, potentially via non-HDAC inhibitory mechanisms.
Conclusions:
- Dietary SCFAs exhibit promising SERD-like activity, offering a potential therapeutic strategy for endocrine-resistant ERα-positive breast cancer.
- High-fiber diets, which promote SCFA production, may hold clinical relevance for managing resistant breast cancer.
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