Targeting Histone Abnormality in Triple Negative Breast Cancer
Technical Report,01 Aug 2014,31 Jul 2018
University of Pittsburgh Pittsburgh United States
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The main goal of this collaborative project is to combine complementary expertise and strength from two PIs to develop a novel, conceptual, and most importantly, testable plan for a new approach to breast cancer biology and treatment. During the entire grants period of performance, the PIs worked closely together to decipher the scientific mechanisms underlying the proposed aims of how histone abnormality contributes to development of TNBC and explore how to combine epigenetic agents with other types of therapeutic drugs in the most favorable strategy against TNBC. The joint research team has revealed that enhanced interaction between two important epigenetic modifiers, HDAC5 and LSD1, stabilizes LSD1 protein that could in turn facilitates TNBC tumor growth and progression. The advanced studies have characterized the proteinscomplexes associated with key regulatory element at HDAC5 promoter, and identified that sulforaphaneSFN, a natural bioactive HDAC inhibitor, was able to destabilize LSD1 protein through downregulation of HDAC5 transcription. This research also shed novel light on how to combine SFN with LSD1 inhibitor to enhance antineoplastic efficacy against TNBC tumor. Furthermore, our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and demonstrated that inhibition of LSD1 reactivates expression of key cytotoxic T cell attracting chemokines which in turn augments sensitivity of TNBC to immune checkpoint blockade therapy. Adequate progress and accomplishments have been achieved towards the proposed aims, and the research funds has been spent effectively as expected during the entire award period. With this funding support, we have published multiple original research papers in top-tier cancer research journals and presented the research outcomes at national cancer research conferences.
- Medicine and Medical Research