Abstract 5196: Vorinostat exhibits anticancer effects through modulation of nuclear receptors and tumor suppressor genes in sub-types of triple negative breast cancer cells

Abstract

Abstract Aberrantly expression of histone deacetylases (HDAC) play a critical role in tumorigenesis. The expression of individual HDACs has been shown to correlate to decreases in both, disease-free and overall survival, thus targeting HDACs is emerging as a new therapy for cancer. Histone acetylation is associated with elevated transcription, while deacetylation is associated with gene repression. Emerging evidence suggests their role in triple negative breast cancer (TNBC) progression. TNBC is an aggressive type of cancer that has poor prognosis and molecular studies have shown several subtypes within TNBC. These cancers lack targeted treatments and several options used such as, PARP inhibitors, angiogenesis inhibitors, androgen receptor inhibitors and others have shown limited efficacy, however histone deacetylase inhibitors are showing promising results in clinical trials. Vorinostat, a histone deacetylase inhibitor, also known as suberanilohydroxane acid (SAHA) was approved by the FDA for treatment of cutaneous T cell lymphoma. In this study, vorinostat was investigated in subtypes of TNBC cell lines, MB231(MSL) and two basal-like 2 TNBC cell lines, HCC70 and HCC1806. Cells were treated with vorinostat for 24 hrs. Vorinostat significantly up-regulated the tumor suppressor gene NR4A1 by 20 fold, NR4A3 by 10 fold and AR5A by 5 fold. RORα gene had the highest up-regulation, 60 fold, whereas PPARγ 4.5 fold. Estrogen related receptor A, ESRRA was also up-regulated in HCC70 cells. A decrease in expression was noted in DDX5, which is known to be elevated in basal-like tumors. A different profile was noted in the MB231 TNBC cells. Vorinostat also decreased growth and cell invasion, which shows its functional effects on these aggressive TNBC cell lines These changes suggest that vorinostat, which is currently in clinical trials for TNBC may be exerting its effect through modulation of orphan nuclear receptors and reactivation of tumor suppressor genes through epigenetic mechanisms. Further studies are needed to determine other signaling pathways modulated by this HDAC inhibitor. Citation Format: Fatemeh NouriEmamzadeh, Beverly Word, Ebony Cotton, Kai Littlejohn, Gustavo Miranda-Carboni, Beverly Lyn-Cook. Vorinostat exhibits anticancer effects through modulation of nuclear receptors and tumor suppressor genes in sub-types of triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5196.