Magee-Womens Research Institute & Foundation

The study of breast cancer epigenetics--meaning literally the various chromatin codes "above" the DNA sequencing --help us understand how tumorigenic factors alter gene expression within breast cancer cells. We now know that when we take active control of epigenetic defects, we can literally improve breast cancer prevention and control.
Yi Huang, MD, PhD

Research in Brief

Dr Huang’s research interests focus on the role of histone modification in breast cancer development. There is a growing body of evidence to suggest that changes in the activity of chromatin-modifying enzymes contribute to uncontrolled breast cell proliferation and tumorigenesis. Our main research objective is to define, in depth, the mechanisms and biological consequences of functional interplay between key histone enzymes in breast cancer growth and metastasis. We are also interested in identifying novel, small molecule reagents that act as selective inhibitors of important chromatin-modifying enzymes to target more specifically the small regions of chromatin and the subset of genes that are associated with most prominent alterations in the breast cancer genome. Our recent work indicated that activities of histone lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are functionally linked in breast cancer, especially in triple negative breast cancer (TNBC). Clinically, TNBC is more aggressive, and distant visceral metastases are more common, in comparison with non-TNBC counterparts. TCGA data suggest that LSD1 is highly expressed in TNBC. We demonstrated that LSD1 inhibition in combination with HDAC inhibition displays superior synergy in blocking growth and inducing expression of aberrantly silenced genes in TNBC cells. We are investigating the precise mechanisms contributing to orchestrated crosstalk between histone modifiers in breast cancer and determining how the dysregulated interaction of histone-modifying enzymes leads to aberrant gene silencing and the aggressive phenotype of TNBC. We are also studying whether targeting crosstalk between epigenetic modulators and immune compartments could serve as a novel therapeutic approach for poorly immune responsive breast cancer patients. We have demonstrated that inhibition of LSD1 reactivates key immune checkpoint regulator and cytotoxic T cell-attracting chemokines, which in turn augments sensitivity of TNBC to immune checkpoint blocking antibody. These novel findings suggest that LSD1 inhibition may be an effective adjuvant treatment with immunotherapy as a novel management strategy for poorly immunogenic breast tumors.