Functions of BRD8 in HR+/HER2+ breast cancer

BRD8 在 HR /HER2 乳腺癌中的功能

基本信息

批准号：
10675821
负责人：
Wei Xu
金额：
$ 41.9万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2023-03-10 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675821
关键词：
ATAC-seq Ablation Aftercare BT 474 Biologic Characteristic Bromodomain Cell Line Cells Chromatin Clinical Compensation Complex Data Development ERBB2 gene Endocrine Epigenetic Process Estrogen Antagonists Estrogen Receptors Foundations Fulvestrant Genes Growth Heterogeneity Hormone Receptor Human Immunofluorescence Immunologic Impairment Investigation Knock-out Lead Link MAP Kinase Gene Mammary Neoplasms Measures Mediating Modeling Molecular Organoids Pathway interactions Patient-Focused Outcomes Patients Phenotype Phosphorylation Pre-Clinical Model Progesterone Receptors Prognosis Proteins Proto-Oncogene Proteins c-akt Receptor Activation Receptor Signaling Regimen Resistance Role Signal Pathway Signal Transduction Specimen Testing The Cancer Genome Atlas Trastuzumab Treatment Protocols Variant Xenograft procedure digital genome-wide histone acetyltransferase hormone sensitivity hormone therapy improved in vitro Model in vivo inhibitor insight knock-down lapatinib loss of function malignant breast neoplasm novel partial response patient subsets personalized medicine research clinical testing resistance mechanism response single nucleus RNA-sequencing single-cell RNA sequencing success targeted agent targeted treatment transcription factor transcriptome treatment response tumor tumor growth tumor xenograft

项目摘要

PROJECT SUMMARY The outcome for patients with HER2-positive breast cancer (BC) has been significantly improved with the use of HER2-directed agents; however, hormone receptor (HR)+/HER2+ BCs that express both HR and HER2 are less responsive to anti-HER2 therapies as compared with HR-/HER2+ BC. Combined endocrine therapy plus anti-HER2-targeted therapy have been clinically investigated, but only a small subset of patients benefit from the treatment, indicating that HR+/HER2+ tumors have different biological characteristics, such as ER and HER2 signaling crosstalk. Dual HER2-blockade induces a Luminal A-like phenotype both in patients’ tumors and in in vitro models. However, the molecular mechanism underlying activation of ER signaling by anti-HER2 agents remains unclear. Using single cell RNA-sequencing (scRNA-seq), we identified Bromodomain Containing Protein 8 (BRD8) as an essential hub bridging HER2 and ER signaling pathways. We found that, BRD8, a component of p400 histone acetylase complex, was rapidly induced by treatment with a variety of anti-HER2 agents including neratinib, lapatinib and trastuzumab and that BRD8 is at the high hierarchy of ER activation in responsive to HER2 blockade. Furthermore, BRD8 regulates other growth promoting pathways in addition to ER. BRD8 knockout significantly impairs growth of a fulvestrant-resistant cell line and xenografts, and BRD8 knockdown enhances the sensitivity of HR+/HER2+ cells to HER2-targeting agents. These preliminary data lead to the hypothesis that BRD8 is an essential hub linking ER and HER2 pathways and BRD8 mediates ER activation in response to HER2 blockade in HER2+ cells. Therefore, combinatory BRD8 ablation with HER2 blockade should be effective for treating HR+/HER2+ BC. We propose three aims to test our hypothesis: (1) to elucidate the mechanism of BRD8 activation by anti-HER2 agents in HER2+ cells at the single cell level; (2) to define the roles of BRD8 in ER signaling activation and ER-independent functions upon HER2 blockade; (3) to test whether ablation of BRD8 sensitizes HR+/HER2+ BC to anti-HER2 blockade. The studies will reveal, at single-cell level, the cell-cell variability of BRD8 induction by anti-HER2 agents, and the novel functions of BRD8 in mediating ER/HER2 signaling crosstalk and ER-independent growth promoting functions. The mechanistic insights will lay foundation for developing combinatory BRD8 ablation and HER2 blockade therapy as a new treatment regimen for HR+/HER2+ BC.

项目概要 HER2 阳性乳腺癌 (BC) 患者的预后已显着改善使用针对 HER2 的药物；然而，同时表达 HR 和 HER2 的激素受体 (HR)+/HER2+ BC 与 HR-/HER2+ BC 联合治疗相比，HER2 对抗 HER2 治疗的反应较差。疗法加抗 HER2 靶向疗法已经进行了临床研究，但只有一小部分患者从治疗中受益，表明 HR+/HER2+ 肿瘤具有不同的生物学特性 ER 和 HER2 信号串扰等特征，双重 HER2 阻断可诱导 Luminal A 样信号。然而，患者肿瘤和体外模型中的表型却是潜在的分子机制。使用单细胞 RNA 测序来激活 ER 信号传导仍不清楚。 (scRNA-seq)，我们确定含溴结构域蛋白 8 (BRD8) 是桥接 HER2 的重要枢纽我们发现，BRD8是p400组蛋白乙酰化酶复合物的一个组成部分。通过多种抗 HER2 药物（包括来那替尼、拉帕替尼和曲妥珠单抗，并且 BRD8 处于对 HER2 阻断作出反应的 ER 激活的高层。此外，除了 BRD8 敲除之外，BRD8 还调节其他生长促进途径。显着损害氟维司群耐药细胞系和异种移植物的生长，以及 BRD8 敲低增强 HR+/HER2+ 细胞对 HER2 靶向药物的敏感性。假设 BRD8 是连接 ER 和 HER2 通路的重要枢纽，并且 BRD8 介导 ER HER2+ 细胞中 HER2 阻断反应而激活，因此，将 BRD8 消除与 HER2 组合。封锁应该对治疗 HR+/HER2+ BC 有效。我们提出三个目标来检验我们的假设：(1) 在单细胞水平上阐明抗 HER2 药物在 HER2+ 细胞中激活 BRD8 的机制； (2) 定义 BRD8 在 ER 信号激活和 HER2 上的 ER 独立功能中的作用阻断；(3) 测试 BRD8 的消融是否使 HR+/HER2+ BC 对抗 HER2 阻断敏感。研究将在单细胞水平上揭示抗 HER2 药物诱导 BRD8 的细胞变异性，以及 BRD8 在介导 ER/HER2 信号串扰和 ER 独立生长中的新功能促进功能的机制见解将为开发组合 BRD8 消融奠定基础。 HER2 阻断疗法作为 HR+/HER2+ BC 的新治疗方案。