Project 1

项目1

基本信息

批准号：
10762160
负责人：
ERNEST MARTINEZ
金额：
$ 14.61万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762160
关键词：
Acetylation Acylation Affect African African ancestry Arginine Automobile Driving Binding Biological Biological Markers Biology Biopsy Specimen Breast Cancer Cell Breast Epithelial Cells Cell Proliferation Cell physiology Cells Complex Data EP300 gene ERBB2 gene Epigenetic Process Estrogen receptor positive European Gene Expression Regulation Genes Genetic Genetic Transcription Goals Histone Acetylation Histone H3 Histones Human Individual Invaded Isomerism Lysine MCF10A cells Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Metabolic Activation Molecular Mutation Neoplasm Metastasis Oncogenic PIK3CA gene PIK3CG gene Pathway interactions Peptidylprolyl Isomerase Prognosis Publishing Reader Recurrence Regulation Resistance Role Signal Pathway Signal Transduction Site Testing Therapeutic Tissue Banks Transactivation Transcriptional Activation Tumor Cell Biology Woman Writing XCL1 gene cancer cell cell immortalization cell transformation cell type cofactor determinants of treatment resistance drug development druggable target improved malignant breast neoplasm mammary new therapeutic target notch protein overexpression programs promoter recruit stem stem cell self renewal therapeutic target therapy resistant tumor

项目摘要

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.

大多数Luminal B乳腺癌（LBBC; ER+，HER2-WT，KI67> 14％）都带有良好的提示。然而，大约20％的LBBC具有高度侵略性，对当前疗法具有抗性。较差的LBBC 不成比例地影响非洲血统的妇女；大多数是MYC激活的。有很多失败的治疗靶向MYC的尝试失败。这些尝试部分失败了，部分原因是我们目前无法在机械或治疗上，将MYC的癌症促进活动与正常必需品分开细胞功能。在初步数据中，我们表明MYC的癌症转化能力取决于三个 MYC（K149，K158和K323）的赖氨酸（K）保留，是组蛋白的主要底物乙酰转移酶（帽子）P300和GCN5；这些特定站点的个人替换阻碍了 MYC转化人类乳腺细胞。在我们的初步数据的指导下，我们旨在剖析辅助因子这些Myc乙酰基-K（ACK）保留的分子机制可促进细胞转化和 LBBC的启动和进展。我们的长期目标是确定新的“可药”目标以提高生存受侵略性LBBC影响最大的女性；因此，我们的研究将集中于非洲妇女。在我们的初步数据的指导下，我们假设基因选择性myc-ack信号通路驱动了抗治疗的LBBC的侵袭性肿瘤细胞生物学，涉及转录辅助因子和表观遗传学在MYC和HISSONES上“写入”和/或“读” ACK标记的核心节目，可能包括辅助因子 LBBC中的MYC过表达，例如PIN1，GCN5，P300和/或YEATS2。在这里，我们将调查 MYC-ACK依赖信号传导在腔内乳细胞转化中的作用和侵略性进展腔内癌细胞和LBBC肿瘤以及鉴定辅助因子和机制。这种新的MYC致癌信号通路的表征可以提供生物标志物和/或治疗非洲妇女的LBBC目标。 AIM 1将测试Myc-Ack依赖信号的影响乳腺上皮细胞转化以及非洲妇女LBBC的侵略性生物学。目的 2将表征转化的乳腺中MYC-ACK依赖基因调节的分子机制上皮细胞，LBBC细胞和来自非洲妇女的肿瘤。