Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers
Abstract
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 H/D 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1006414
Entities
People
- Dewey G. Mccafferty
Organizations
- Duke University