Project 1

大多数腔型B型乳腺癌(LBBC；ER+，HER2-wt，Ki67&Gt；14%)预后良好。然而， 大约20%的LBBC患者对当前的治疗方法具有高度的攻击性和抵抗力。预后不佳的LBBC 对非洲裔妇女造成不成比例的影响；大多数是由MYC激活的。已经有很多 以治疗为靶点的MYC尝试失败。这些尝试之所以失败，部分原因是我们目前无法 将MYC的促癌活性从机械或治疗上与其正常的基本成分分开 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(K149、K158和K323)的赖氨酸(K)残基，是组蛋白乙酰化的主要底物 乙酰基转移酶(HATS)p300和GCN5；这些特定位点的单独替换阻止了 MYC转化人类乳腺细胞。在我们的初步数据的指导下，我们的目标是剖析辅助因素 以及这些MYC乙酰-K(ACK)残基促进细胞转化和 LBBC的发起和发展。我们的长期目标是确定新的“可用药”靶点，以提高存活率 因此，我们的研究将重点放在非洲裔妇女身上。 根据我们的初步数据，我们假设一个基因选择性的myc-ack信号通路驱动着 耐药LBBC的侵袭性肿瘤细胞生物学及其涉及转录辅助因子和表观遗传学 “写”和/或“读”MYC和组蛋白上的ACK标记的协调节器，可能包括辅因子辅因子- 在LBBC中高表达MYC，如Pin1、GCN5、p300和/或YEATS2。在这里，我们将调查 MYC-ACK依赖信号在腔内乳腺细胞转化和侵袭性进展中的作用 腔癌细胞和LBBC肿瘤，以及确定相关的辅助因素和机制。 这一新的MYC致癌信号通路的特征可能提供生物标志物和/或治疗 LBBC在非洲裔妇女中的目标。目标1将测试依赖于MYC-ACK的信号在 乳房上皮细胞转化和LBBC侵袭性生物学在非洲裔妇女中的作用。目标 2将表征转化乳腺中MYC-ACK依赖的基因调控的分子机制 上皮细胞和LBBC细胞以及非洲裔妇女的肿瘤中。

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.