Targeting histone abnormality in triple negative breast cancer
Technical Report,01 Aug 2016,31 Jul 2017
University of Pittsburgh Pittsburgh United States
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In this funding period, initiating PI and partnering PI collaborated to test the hypothesis that silencing of key tumor suppressive genes by enhanced crosstalk between LSD1 and HDAC is a unique epigenetic mechanism promoting TNBC growth, and blockade of theHDAC5-LSD1 axis results in profound inhibition of TNBC growth and metastasis. In this funding cycle, we found that the expression levels ofLSD1 and HDAC5 are negatively associated with T-cell attracting chemokines and PD-L1 in clinical TNBC specimens. Further study found that Inhibition of LSD1 significantly increased expression of T-cell chemokines and PD-L1 in TNBC cell lines. Combination of LSD1 inhibitor andPD-1PD-L1 blockade exhibited significant synergy in hindering breast cancer progression. We also explore the roles of LSD1 homolog, LSD2KDM1B, in breast oncogenesis. We found that overexpression of LSD2 protein significantly altered expression of key important epigenetic modifiers such as LSD1, HDAC5, etc., promoted cellular proliferation and augmented formation of larger colonies in soft agar. We also demonstrated that LSD2 overexpression in MDA-MB-231 cells facilitated mammosphere formation, enriched CD49fEpCAM- subpopulation and induced expression of pluripotent stem cell markers Nanog and Sox2. Stable overexpression of LSD2 resulted in accelerated growth ofMDA-MB-231 xenograft tumors in nude mice.
- Medicine and Medical Research