Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers
Technical Report,30 Sep 2014,29 Sep 2015
Duke University Durham United States
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Our goals for this project are to explore LSD1 inhibition of protein-protein interactions as a potential therapy for ER- breast cancer, ameliorating iLCC for in vivo use, and using novel proteomics approaches to identify coregulatory proteins interacting with ER and LSD1 in ER cells and deduce how the complement of LSD1 associating proteins change in ER- cancers. We have made significant progress on the aims this project,specifically by examining the effects of small molecule, LSD1-selective and broad-spectrum histone demethylase inhibitors on breast cancer tumor growth as compared to iLCC. Using protein engineering, and HD exchange MS,we identified the LSD1 alpha helical coiled-coil as a central mediator of ER signaling and coregulatory protein recruitment. Using siRNA knockdown and a newly identified highly selective inhibitor of the LSD1 demethylase active site chemistry, we showed that loss of LSD1 or inhibition of the LSD1-CoREST complex by iLCC inhibits breast cancer proliferation, but the antiproliferative effects of tranylcypromine or pargyline exhibit antiproliferativeeffects in ER and ER- breast cancers by a secondary mechanism requiring LSD1 as a scaffolding element.