Co-Oncogenic Role of ECD in HER2-Driven Breast Cancer

ECD 在 HER2 驱动的乳腺癌中的共致癌作用

基本信息

批准号：
10474522
负责人：
VIMLA BAND
金额：
$ 7.68万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474522
关键词：
Address Applications Grants Breast Cancer Cell Breast Cancer Patient Cancer Etiology Cell Culture System Cell Cycle Progression Cells Cellular Stress Cessation of life Clinical Combined Modality Therapy Data Data Set Disease Doxycycline ERBB2 gene Exhibits Future Homologous Gene Human Hyperplasia Inter-tumoral heterogeneity Lesion Link Malignant Neoplasms Malignant neoplasm of pancreas Mammary Gland Parenchyma Mammary gland Messenger RNA Metabolism Modeling Molecular Molecular Profiling Mus Mutation Nature Oncogenic Organoids Outcome PIK3CA gene Pancreas Pathway interactions Patients Pertuzumab Prognosis Prognostic Marker Protein Overexpression Proteins Receptor Protein-Tyrosine Kinases Resistance Role S-Phase Fraction Stains Stomach Subgroup Testing Tetanus Helper Peptide The Cancer Genome Atlas Therapeutic Tissue Microarray Transgenes Transgenic Mice Trastuzumab Validation WNT Signaling Pathway Woman base beta catenin breast cancer survival c-myc Genes cancer diagnosis cohort combinatorial design epithelial to mesenchymal transition experimental study fly gene product glucose uptake improved inhibitor lapatinib malignant breast neoplasm mammary mammary epithelium metabolomics mouse model neoplastic novel novel therapeutics overexpression prognostic success targeted treatment tool transcriptome sequencing tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Breast cancer (BC) is a genetically and clinically heterogeneous disease and molecular profiling has identified five major subtypes of BC. One subtype, the HER2+ (~20%) BC is driven by the receptor tyrosine kinase HER2. HER2-targeted therapies have significantly improved the survival of these patients, however, most advanced stage patients are incurable, and acquisition of resistance is universal. Recently, it has been shown that about 30% of HER2+ BC patients have activating mutations in PIK3CA. HER2+/PIK3CA double-transgenic mouse tumors are completely resistant to trastuzumab combination therapy but adding a PI3K inhibitor reversed the resistance. Therefore, elucidating additional co-oncogenic pathways that collaborate with HER2 to facilitate and/or enhance HER2-driven oncogenesis, is likely to broaden the potential to design combinatorial therapeutic approaches against advanced HER2-driven BC and to forestall and/or overcome resistance to existing therapies. This R03 proposal focuses on demonstrating a novel co-oncogenic role of ECD (Ecdysoneless) in HER2+ BC. ECD protein and mRNA is overexpressed in BC, particularly in HER2+, correlating with poor prognostic markers and shorter disease-free and overall survival. To directly address the role of ECD in BC, we generated mice with a mammary epithelium-targeted inducible (Tet-off) human ECD transgene (ECDTg). Significantly, 85% of ECDTg mice exhibit mammary hyperplasia in 5-6 months, and 33% show heterogeneous tumors within 18- 24 months. Importantly, 85% of the remaining mice show pre-neoplastic lesions. Significantly, ECDTg tumors showed increased c-MYC and β-catenin expression. Functionally, decrease in ECD levels decreased glucose uptake, suggesting a potential link of ECD and metabolism. Lack of HER2 overexpression in ECDTg tumors dictates the need to cross ECDTg model with huHER2Tg mice that recapitulates the co-overexpression of ECD seen in HER2+ BC patients. Thus, the rationale for studies proposed in this R03 grant application is very strong. Based on these data, we hypothesize that ECD co-overexpression in HER2-driven oncogenesis promotes further tumorigenesis and generating ECD;huHER2 double transgenic mice will test this hypothesis. Further characterization of the ECDTg vs. ECD;huHER2Tg models will help delineate the molecular mechanism of poor outcomes in patients overexpressing both ECD and HER2. Aim 1 will examine the co-oncogenic role of ECD in HER2-driven breast cancer using mouse mammary gland-targeted ECD transgene overexpression. Aim 2 will use unbiased approaches (RNA-seq and metabolomics) to delineate the mechanism of ECD- and HER2- dependent oncogenesis in BC. Validation of our hypothesis will help us understand how ECD overexpression promotes HER2-driven BC with worse outcomes. A validated ECD;huHER2Tg model will provide an invaluable tool to understand the mechanistic basis of their co-oncogenesis and future testing of novel therapeutics against HER2+/ECD-overexpressing BC and to address therapy resistance. Success of our studies may also open broader avenues for other malignancies where ECD overexpression is associated with tumor progression.

项目概要/摘要乳腺癌 (BC) 是一种遗传和临床异质性疾病，分子分析已确定 BC 的五种主要亚型。其中一种亚型 HER2+ (~20%) BC 由受体酪氨酸激酶 HER2 驱动。 HER2 靶向治疗显着改善了这些患者的生存率，然而，最先进的治疗近来的研究表明，该阶段的患者是无法治愈的，并且耐药性的获得是普遍存在的。 30% 的 HER2+ BC 患者在 HER2+/PIK3CA 双转基因小鼠中存在激活突变。肿瘤对曲妥珠单抗联合治疗完全耐药，但添加 PI3K 抑制剂逆转了这种情况因此，阐明与 HER2 协同促进的其他共致癌途径。和/或增强 HER2 驱动的肿瘤发生，可能会扩大设计组合疗法的潜力针对晚期 HER2 驱动的 BC 的方法，并预防和/或克服对现有疗法的耐药性。该 R03 提案的重点是展示 ECD（Ecdysoneless）在 HER2+ 中的新型协同致癌作用 BC 中 ECD 蛋白和 mRNA 过度表达，尤其是 HER2+ 中，与不良预后相关。为了直接解决 ECD 在 BC 中的作用，我们生成了。具有乳腺上皮靶向诱导型 (Tet-off) 人 ECD 转基因 (ECDTg) 的小鼠显着，85%。的 ECDTg 小鼠在 5-6 个月内表现出乳腺增生，33% 在 18 个月内表现出异质性肿瘤重要的是，85% 的剩余小鼠表现出明显的 ECDTg 肿瘤。显示 c-MYC 和 β-catenin 表达增加从功能上讲，ECD 水平降低会降低血糖。摄取，表明 ECDTg 肿瘤中缺乏 HER2 过度表达。表明需要将 ECDTg 模型与 huHER2Tg 小鼠交叉，以概括 ECD 的共过表达因此，该 R03 拨款申请中提出的研究的理由非常充分。基于这些数据，我们大胆认为 ECD 在 HER2 驱动的肿瘤发生中的共过表达可进一步促进肿瘤发生和产生ECD；huHER2双转基因小鼠将进一步检验这一假设。 ECDTg 与 ECD;huHER2Tg 模型的表征将有助于描述不良的分子机制目标 1 将检查 ECD 的共同致癌作用。使用小鼠乳腺靶向 ECD 转基因过表达来治疗 HER2 驱动的乳腺癌，目标 2。使用公正的方法（RNA-seq 和代谢组学）来描述 ECD- 和 HER2- 的机制 BC 中依赖的肿瘤发生对我们的假设的验证将帮助我们了解 ECD 过度表达是如何发生的。促进 HER2 驱动的 BC，结果更差。经过验证的 ECD；huHER2Tg 模型将提供宝贵的信息。了解其共癌发生的机制基础和未来针对新疗法的测试的工具 HER2+/ECD 过度表达 BC 和解决治疗耐药性也可能会取得成功。为 ECD 过度表达与肿瘤进展相关的其他恶性肿瘤提供更广泛的途径。