| dc.description.abstract | Breast cancer is one of the most common cancers affecting women in the United States. Hormone receptor positive (HR+) breast tumors are the most prevalent, accounting for 70% of breast cancer cases. Therapies that target hormone receptors such as the estrogen receptor (ER) or that target estradiol synthesis are most commonly used to treat these patients; however, some patients may develop resistance to these treatments. One mechanism of resistance is the development of a constitutively active estrogen receptor alpha (ERα, ESR1) due to somatic mutations in the ligand binding domain (LBD). The most common of these mutations are ESR1- Y537S and ESR1-D538G. Fulvestrant, a hormone therapy, is used to treat patients with these mutations. Previous studies have shown that histone deacetylase (HDAC) inhibitors downregulate ESR1. Some dietary derived short chain fatty acids: butyrate, propionate, and acetate are reported to exhibit HDAC inhibitory activity. We investigated their effects as SERDs in MCF-7 and T47D cells expressing both wild-type and mutant ESR1. Propionate and butyrate exhibited similar induction of histone acetylation. Although acetate induced ESR1 degradation, acetate may not function independently of HDAC inhibition to downregulate ESR1. HDAC inhibitors: Panobinostat, Vorinostat, and Entinostat are currently being investigated as breast cancer treatment in clinical trials. We observed that Panobinostat, Vorinostat, and Entinostat downregulated wild-type and mutant ESR1and induced histone acetylation. These results suggest that HDAC inhibitors act as SERDs and may be clinically efficacious for treating ER-positive endocrine resistant breast cancer patients and this is currently being investigated. | |
