Targeting Histone Abnormality in Triple Negative Breast Cancer
Technical Report,01 Aug 2015,31 Jul 2016
University of Pittsburgh Cancer Institute Pittsburgh United States
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Increasing lines of evidence showed that epigenetic regulation of TNBC proliferation and gene expression could provide novel targets for molecularly directed therapies for this devastating disease. In the first year of this award, our team collaborated with Dr. Huangs lab to demonstrate the coordinated overexpression of HDAC5 and LSD1 proteins in human primary breast tumor specimens. By using in vitro and in vivo models, we identified that sulforaphane SFN, a natural bioactive HDAC inhibitor, destabilized LSD1 protein through downregulation of HDAC5 transcription, and combined use of SFN with a potent LSD1 inhibitor HCI-2509 significantly enhanced antineoplastic efficacy of SFN in MDA-MB-231 xenografts in mice. On the basis of these novel findings, we carried out microarray assays to address the global effect of HDAC5-LSD1 axis on gene expression in TNBC cells. This study successfully identified a subset of genes including a group of tumor suppressor genes whose expression was regulated by HDAC5-LSD1 signaling. During this funding period, our lab also explored the molecular mechanism of SFN induced suppression of HDAC5 transcription and performed the histological and pathological examinations of tissues, and interpretation of the results generated from in vivo studies. The collaborative studies between two labs have resulted in publication of a research article in Oncogene.
- Medicine and Medical Research