Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer

Early stage estrogen receptor alpha (ER alpha, ESR1)-positive breast cancer patients can develop more aggressive endocrine-resistant tumors that express constitutively active mutant forms of ER alpha including ER alpha-Y537S and ER alpha-D538G. These patients are treated with selective ER down regulators (SERDs) such as the ER alpha antagonist fulvestrant. Previous studies show that histone deacetylase (HDAC) inhibitors downregulate ER alpha 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 ER alpha-D538G and ER alpha-Y537S. The SCFAs exhibited SERD-like activity in both cell lines expressing wild-type and mutant ER alpha. The results for propionate and butyrate correlated with parallel induction of histone acetylation and this was also observed for the HDAC in-hibitors Panobinostat, Vorinostat and Entinostat which also downregulated wild-type and mutant ER alpha and induced histone acetylation. Although acetate induced ER alpha 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.

Automated summary

The study found that certain dietary-derived short chain fatty acids exhibit SERD-like activity and may be beneficial for treating ER-positive endocrine resistant breast cancer patients. In addition, histone deacetylase inhibitors also showed similar mechanisms of action.