Epigenetic drugs, such as histone deacetylase inhibitors (HDACi), are continuing to emerge as promising therapies for various cancers. These drugs, including FDA-approved vorinostat, are capable of multiple actions and considered to be multifunctional. Histone deacetylases (HDAC) are chromatin-modifying enzymes that are involved in various cellular events, such as tissue differentiation, autophagy, apoptosis, migration, mitosis and angiogenesis. High levels of HDACs have been detected in several cancers. Early studies in our laboratory showed different effects by vorinostat on global HDAC activity in several triple-negative breast cancer (TNBC) subtypes. This study focused on HDAC 7, which has been associated with increases in cancer stem cells and poor prognosis. Cancer stem cells play an important role in cancer resistance to therapy. Histone deacetylase inhibitors are emerging as therapy for triple-negative breast cancer, which is currently an unmet need in women's health due to the lack of targeted therapies. This study investigated the effects of vorinostat on apoptosis and the modulation of HDAC 7 expression in two subtypes of triple-negative breast cancers, MB231(MSL) and HCC70 (BL-2). Using caspase 3/7 assays vorinostat induced apoptosis. Additionally, flow cytometry and immunostaining were conducted to determine vorinostat's effects on expression of two cancer stem cell (CSC) markers, CD44 and CD24. Western blot and real-time PCR showed a significant decrease (10-fold) in the expression of HDAC 7 by vorinostat in HCC70 cells. A modest decrease (3-fold) was also observed in MB231 cells. CD44 expression was deceased by vorinostat in MB231 cells. This study demonstrated that vorinostat exerts its anticancer effects through several mechanisms, such as inducing apoptosis, downregulating HDAC 7 and decreasing cancer stem cells. This therapy could be beneficial for subtypes of TNBC, such as HCC70, an aggressive basal-like 2 cell line from an African American.

Citation Format: Fatemeh Nouri Emamzadeh, Anfernee Hawkins, Gustavo Miranda-Carboni, Rhonda Moore, Beverly Word, Beverly Lyn-Cook. Modulation of HDAC activity in subtypes of triple-negative breast cancer: Effects of vorinostat on HDAC 7 expression and cancer stem cells progression [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C109.