Targeting Histone Abnormality in Triple-Negative Breast Cancer
Technical Report,01 Aug 2014,31 Jul 2015
University of Pittsburgh Cancer Institute Pittsburgh
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Like other cancers, triple negative breast cancer TNBC develops as a consequence of cumulative genetic and epigenetic changes. The goal of this funded proposal is to understand how changes in interaction of chromatin-remodeling enzymes contribute to TNBC development and to test novel targeted combination approaches of epigenetic drugs in restoration of aberrantly silenced tumor suppressor genes and inhibition of breast tumor growth. Our previous work suggested that TNBC had enhanced crosstalk between histone enzymes LSD1 and HDAC5 that promoted aberrant gene silencing and TNBC cell growth. Our ongoing studies demonstrated that crosstalk between LSD1 and HDAC5 may represent a novel and effective target for therapeutic target for TNBC. We further identified that sulforaphane, a natural HDAC inhibitor found in cruciferous vegetables, uniquely suppressed HDAC5 mRNA expression that facilitated LSD1 protein destabilization. Sulforaphane significantly inhibited growth in cultured breast cancer cells and MDA-MB-231 xenografts. Combined use with a novel LSD1 inhibitor, HCI-2509, significantly promoted antineoplastic efficacy of sulforaphane. Moreover, microarray screening in HDAC5-KD and LSD1-KD cells identified a unique subset of genes whose expression was co-regulated by HDAC5 and LSD1 signaling pathways. These novel findings suggest that HDAC5-LSD1 axis may represent a novel and effective therapeutic target for TNBC.