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New Epigenetic Therapeutic Intervention for Metastatic Breast Cancer

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Technical Report,15 Mar 2015,14 Mar 2018

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University of Kentucky Lexington United States

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Triple-negative breast cancer TNBC distinguishes 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, and cancer stem cell-like traits that permit tumor dissemination and growth at distant sites. The Wnt pathways are important for EMT. We recently discovered that Wnt5a and its transcription factor Twist are markedly over-expressed 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 factorco-activator activity in gene activation, a key function required for the prolonged expression of inflammatory cytokines that fuel TNBC cells proliferation and spreading.

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