New Epigenetic Therapeutic Intervention for Metastatic Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of human cancer and has no any available targeted therapy. The only available treatment today for advanced stage TNBC patients is chemotherapy, which has deleterious side effects and is not effective in most cases. Breast cancer is divided into five major subtypes based on gene expression profiling including: luminal A, luminal B, ErbB2, normal-like, and basal-like. Basal-like breast cancer is defined by expression of markers characteristic of basal/myoepithelial cells, and lack of the expression of three receptors, i.e., estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2/neu), hence commonly referred to as "triple-negative breast cancer." The most treatments available for breast cancer target these receptors and are thus not applicable for TNBC. TNBC is distinguished from other forms of breast cancer in origination and progression. Likely originated from undifferentiated cancer stem cells, TNBC tumor cells possess many epithelial-mesenchymal transition (EMT) characteristics including invasion, resistance to apoptosis, as well as cancer stem cell (CSC)-like traits that permit tumor dissemination and growth at distant sites. The Wnt pathways are important for EMT. Our recent study has revealed that Wnt5a and its transcription factor Twist are markedly overexpressed in TNBC but not luminal breast cancer cells. We also discovered that constitutively activated NF-kB in TNBC sustains prolonged activation of pro-inflammatory cytokines, enabling rapid spread (metastasis) of TNBC tumors. Notably, the functions of both transcription factors Twist and NF-kB in gene activation require lysine acetylation, which signs to activate the transcriptional machinery in chromatin. This chemical modification enables them to recruit the major transcriptional regulatory co-activator proteins to coordinate target gene activation in the human genome. In this study, we will investigate the underlying mechanism of gene activation in TNBC. We are developing novel small molecule compounds to render the transcription factor/co-activator activity in gene activation, a key function required for the prolonged expression of inflammatory cytokines that fuel TNBC cells proliferation and spreading. Our study should have a major impact on new targeted therapy development to fight against the aggressive TNBC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510044
Entities
People
- Binhua Zhou
Organizations
- United States Army
- University of Kentucky