New Epigenetic Therapeutic Intervention for Metastatic Breast Cancer

Aim 1: Determine the Role of BET Proteins in Gene Transcriptional Activation in TNBC BRD4, via its tandem BrDs, controls gene activation through transcription factor recruitment, enhancer assembly, and activation of transcriptional elongation. To better understand functional differences of the different BET proteins (i.e. BRD2, BRD3 and BRD4), we will characterize their structural mechanisms in gene activation by solving new 3D structures of their BrDs bound to acetylated peptides from histones and key transcription factors in TNBC cells. We will specifically conduct mechanistic investigation of Twist, NF-kB, and STAT3 in their target gene transcriptional activation, which have been shown to contribute to the EMT and CSC-like features, as well as inflammatory nature of TNBC cells. Aim 2: Develop Selective BET BrD Inhibitors Targeting Oncogenesis Gene Activation We will perform target structure-guided development of new chemical inhibitors that selectively target the individual BrDs of BET proteins. These new BrD inhibitors will be fully characterized for their selectivity and potency in vitro and cellular efficacy in control of the gene transcriptional program that dictates EMT and cancer stem cell proliferation and differentiation in TNBC. Aim 3: Characterize the Mechanism of the Transcriptional Program in TNBC Cells Growing evidence show that TNBC is an inflammation-associated disease whose rapid progression of tumor formation and spreading is fueled at the level of gene transcription. Our lead BrD inhibitor impairs Twistdirected transcriptional activation of pro-inflammatory genes and EMT markers in TNBC cells. To determine the underlying mechanisms, we will use newly developed selective BrDis to identify BET protein target genes, and characterize the functional differences of the two BrDs of the BET proteins in gene activation important for the EMT and cancer stem cell properties and inflammation-induced rapid cell growth and metastasis of TNBC. The latter is considered as the root cause of TNBC tumor initiating, metastatic potential and therapeutic resistance properties. We hope that these newly developed BrD inhibitors will help develop more effective and safer drugs against TNBC.