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.

大多数管腔 B 型乳腺癌（LBBC；ER+、HER2-wt、Ki67>14%）预后良好。大约 20% 的 LBBC 具有高度侵袭性并且对当前治疗具有耐药性。非洲裔女性受到的影响尤为严重；大多数是 MYC 激活的。以 MYC 为靶点的治疗尝试失败了，部分原因是我们目前无法做到这一点。从机制上或治疗上将 MYC 的促癌活性与其正常必需的活性区分开来在初步数据中，我们表明 MYC 的癌症转化能力取决于三个因素。 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 GCN5；这些特定位点的单独替换会阻止 MYC 转化人类乳腺细胞在我们初步数据的指导下，我们的目标是剖析辅助因子。以及这些 MYC 乙酰基-K (AcK) 残基促进细胞转化的分子机制我们的长期目标是确定新的“可药物”靶点以提高生存率。受攻击性 LBBC 影响最严重的女性；因此，我们的研究将重点关注非洲裔女性。根据我们的初步数据，我们发现基因选择性 MYC-AcK 信号通路驱动治疗耐药 LBBC 的侵袭性肿瘤细胞生物学和转录涉及辅因子和表观遗传在 MYC 和组蛋白上“写入”和/或“读取”AcK 标记的核心调节器，可能包括辅助因子 co- LBBC 中 MYC 过表达，例如 PIN1、GCN5、p300 和/或 YEATS2。 MYC-AcK 依赖性信号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，并确定所涉及的辅助因子和机制。这种新的 MYC 致癌信号通路的表征可能提供生物标志物和/或治疗 LBBC 在非洲裔女性中的目标目标 1 将测试 MYC-AcK 依赖性信号传导的影响。乳腺上皮细胞转化和非洲裔女性 LBBC 的侵袭性生物学。图2将表征转化乳腺中MYC-AcK依赖性基因调控的分子机制上皮细胞、LBBC 细胞和非洲裔女性肿瘤中。