Project 1

大多数腔型B乳腺癌（LBBC; ER+，HER 2-wt，Ki 67>14%）具有良好的预后。然而，在这方面， 大约20%的LBBC是高度侵袭性的，并且对当前的疗法具有抗性。预后不良LBBC 对非洲裔妇女产生重大影响;大多数是启动了多文化社区的。发生多 针对MYC的治疗尝试失败。这些尝试都失败了，部分原因是我们目前无法 将MYC的促癌活性，从机制上或治疗上， 细胞功能。在初步数据中，我们表明MYC的癌症转化能力依赖于三个因素， MYC的赖氨酸（K）残基（K149、K158和K323），是组蛋白乙酰化的主要底物 乙酰转移酶（HAT）p300和GCN 5;这些特定位点的单独取代阻断了乙酰转移酶（HAT）的能力。 MYC转化人类乳腺细胞。在我们初步数据的指导下，在这里我们的目标是剖析辅因子 以及这些MYC乙酰基-K（AcK）残基促进细胞转化的分子机制， LBBC的起源和发展。我们的长期目标是确定新的“可用药”靶点以提高生存率 因此，我们的研究将侧重于非洲裔妇女。 在我们初步数据的指导下，我们假设基因选择性MYC-AcK信号通路驱动了 治疗抗性LBBC的侵袭性肿瘤细胞生物学，并涉及转录辅因子和表观遗传 在MYC和组蛋白上“写入”和/或“读取”AcK标记的辅助调节因子，可能包括辅助因子， 在LBBC中，MYC过表达，如PIN 1、GCN 5、p300和/或YEATS 2。在这里，我们将调查 MYC-AcK依赖性信号传导在管腔乳腺细胞转化和侵袭性进展中的作用 管腔癌细胞和LBBC肿瘤，以及确定相关的辅因子和机制。 这种新的MYC致癌信号传导途径的表征可以提供生物标志物和/或治疗方法。 在非洲裔妇女中开展LBBC的目标。目标1将测试MYC-AcK依赖性信号传导在 乳腺上皮细胞转化和LBBC在非洲裔妇女中的侵袭性生物学。目的 2将表征转化乳腺癌中MYC-AcK依赖性基因调控的分子机制， 上皮细胞和LBBC细胞以及来自非洲裔女性的肿瘤。

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.