Project 1

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Most luminal B breast cancers (LBBC; ER+, HER2-wt, Ki67>14%) carry a good prognosis. However, approximately 20% of LBBC are highly aggressive and resistant to current therapies. Poor-prognosis LBBC disproportionally impact women of African descent; the majority are MYC-activated. There have been many failed attempts to therapeutically target MYC. These attempts have failed, in part, due to our current inability to separate the cancer-promoting activities of MYC, mechanistically or therapeutically, from its normal essential cellular functions. In preliminary data, we show that the cancer-transforming ability of MYC is dependent on three lysine (K) residues of MYC (K149, K158, and K323) that are major substrates for acetylation by the histone acetyltransferases (HATs) p300 and GCN5; individual substitutions of these specific sites block the ability of MYC to transform human mammary cells. Guided by our preliminary data, here we aim to dissect the cofactors and molecular mechanisms by which these MYC acetyl-K (AcK) residues promote cell transformation and initiation and progression of LBBC. Our long-term goal is to identify new “druggable” targets to improve survival of women most affected by aggressive LBBC; consequently, our studies will focus on women of African-descent. Guided by our preliminary data, we hypothesize that a gene-selective MYC-AcK signaling pathway drives the aggressive tumor cell biology of therapy-resistant LBBC and involves transcription cofactors and epigenetic coregulators that “write” and/or “read” AcK marks on MYC and histones, perhaps including cofactors co- overexpressed with MYC in LBBC, such as PIN1, GCN5, p300, and/or YEATS2. Here, we will investigate the role of MYC-AcK dependent signaling in luminal mammary cell transformation and aggressive progression of luminal cancer cells and LBBC tumors as well as identify the cofactors and mechanisms involved. Characterization of this new MYC oncogenic signaling pathway may provide biomarkers and/or therapeutic targets for LBBC in women of African descent. Aim 1 will test the impact of MYC-AcK dependent signaling in mammary epithelial cell transformation and in the aggressive biology of LBBC in women of African-descent. Aim 2 will characterize the molecular mechanisms of MYC-AcK dependent gene regulation in transformed mammary epithelial cells and in LBBC cells and tumors from women of African-descent.