Functions of BRD8 in HR+/HER2+ breast cancer

BRD8 在 HR /HER2 乳腺癌中的功能

• 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
• 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

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.

项目总结 HER2阳性乳腺癌(BC)患者的预后已显著改善 使用HER2导向的药物；然而，同时表达HR和HER2+的激素受体(HR)+/HER2+BC 与HR-/HER2+BC相比，HER2对抗HER2治疗的反应较差。联合内分泌 治疗加抗HER2靶向治疗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 特性，如ER和HER2信号串扰。双重HER2-阻断诱导管腔A样变 患者肿瘤和体外模型中的表型。然而，潜在的分子机制 抗HER2药物对ER信号的激活作用尚不清楚。使用单细胞RNA测序 (scRNA-seq)，我们发现溴结构域包含蛋白8(BRD8)是连接HER2的重要枢纽 和内质网信号通路。我们发现，P400组蛋白乙酰化酶复合体的一个成分BRD8是 由多种抗HER2药物治疗快速诱导，包括Neratinib，Lapatinib和 曲妥珠单抗和BRD8处于ER激活的较高水平，以响应HER2的阻断。 此外，BRD8除了调节ER外，还调节其他促进生长的途径。BRD8基因敲除 显著抑制耐药细胞系和异种移植瘤的生长，以及BRD8基因敲除 增强HR+/HER2+细胞对HER2靶向药物的敏感性。这些初步数据导致 假设BRD8是连接ER和HER2通路的重要枢纽，BRD8介导ER HER2阻断后HER2+细胞的激活。因此，BRD8和HER2联合消融 阻断治疗HR+/HER2+BC是有效的。我们提出了三个目标来验证我们的假设：(1) 从单细胞水平阐明抗HER2药物激活HER2+细胞BRD8的机制； (2)明确BRD8在ER信号激活中的作用和HER2上的ER非依赖性功能 (3)检测消融BRD8是否使HR+/HER2+BC对HER2受体拮抗剂敏感。这个 研究将在单细胞水平上揭示抗HER2药物诱导BRD8的细胞-细胞变异性，以及 BRD8在介导ER/HER2信号串扰和ER非依赖性生长中的新功能 提升功能。这些机理见解将为开展BRD8联合消融奠定基础 HER2阻断治疗可作为HR+/HER2+BC的新治疗方案。