Role of MYC-MIZ1 signaling and the inflammatory immune microenvironment in Triple-Negative Breast Cancer Racial Disparities

MYC-MIZ1 信号传导和炎症免疫微环境在三阴性乳腺癌种族差异中的作用

• 批准号: 10469706
• 负责人: Vinay Varadan
• 金额: $ 21.87万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469706
• 关键词: African American; American; Biological; Biological Factors; Biological Models; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Burden; Cancer cell line; Cell Line; ChIP-seq; Chemoresistance; Chronic; Clinical; Clinical Management; Clinical Trials; Coculture Techniques; Comprehensive Cancer Center; DNA Methylation; Data; Data Set; Databases; Development; Disease; Disease model; Encyclopedias; Ethnic Origin; Ethnic group; Etiology; European; Event; Exhibits; Gene Expression; Genes; Goals; Grant; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Kansas; Lead; Macrophage Activation; Mediator of activation protein; Modeling; Molecular; Monitor; Obesity; Ohio; Oncogenes; Outcome; Paclitaxel; Pathologic; Pathway interactions; Patients; Phenotype; Population; Process; Prognosis; Prognostic Marker; Recording of previous events; Resistance; Role; Sampling; Signal Transduction; Site; Southwest Oncology Group; Stress; Systems Biology; Testing; Therapeutic; Time; Tissue Sample; Tissues; Tumor Biology; Tumor-infiltrating immune cells; United States; Variant; Woman; Xenograft Model; Xenograft procedure; ZNF151 gene; base; cancer health disparity; chemotherapy; cohort; design; experimental study; gene therapy; genetic manipulation; genome-wide; immunoregulation; improved outcome; lifestyle factors; macrophage; malignant breast neoplasm; monocyte; multiple omics; novel; novel marker; novel therapeutic intervention; patient derived xenograft model; patient population; pre-clinical; racial disparity; repository; response; socioeconomics; targeted treatment; transcriptome; treatment response; triple-negative invasive breast carcinoma; tumor; tumor xenograft; tumor-immune system interactions; tumorigenic

Project Abstract Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with limited treatment options and frequently exhibits resistance to chemotherapy leading to poorer prognosis in TNBC patients. African American (AA) women in the U.S. suffer from higher incidence rates of TNBCs and poorer clinical outcomes as compared to their European American (EA) counterparts. These ethnicity-associated differences in outcomes remain significant after controlling for socioeconomic and treatment variations, suggesting that intrinsic differences in tumor biology exist between AA vs. EA TNBCs and contribute to outcome disparities. To decode the biologic factors contributing to the unequal TNBC burdens, we employed a novel systems biology approach (InFlo) to interrogate transcriptome profiles of TNBCs in AA and EA women, and identified MYC-MIZ1 signaling to be disparately activated in up to 70% of AA TNBCs as compared to only 30% of EA TNBCs. Patients harboring MYC-MIZ1 activated TNBCs exhibited poorer overall survival. Furthermore, we found higher levels of M2 Macrophage infiltration (>2-fold) in TNBCs in AA as compared to EA, suggesting that a tumorigenic immune microenvironment contributes to the disparate cancer burdens in AAs. These findings suggest for the first time, that ethnicity-associated differences in MYC-MIZ1 signaling and inflammatory immune modulation jointly contribute to TNBC outcome disparities. This proposal is fashioned to delineate the biologic role of MYC-MIZ1 signaling and M2 Macrophages in TNBC disparities as follows: Aim 1: Use multi-omics assessments performed in AA and EA primary TNBC tissues and cell line models to decipher the upstream regulators and the downstream mediators of MYC-MIZ1 signaling in TNBCs. We will decode the cross-talk between tumor MYC-MIZ1 signaling and M2 Macrophage infiltration in TNBCs using co- culture experiments. These studies will be the first to establish the regulatory roadmap of MYC-MIZ1 signaling in TNBCs and the mechanisms underlying functional crosstalk between the immune microenvironment and tumor MYC-MIZ1 signaling in AA versus EA TNBCs. Aim 2: Determine whether MYC-MIZ1 signaling modulates TNBC response to chemotherapy using genetic manipulation studies in preclinical cell line, xenograft and PDX model systems. These studies will unravel the functional role of MYC-MIZ1 signaling in conferring chemotherapy resistance in TNBCs, and revealing potentially novel therapeutic strategies in this disease. Aim 3: Evaluate the generality of frequent MYC-MIZ1 signaling activation and increased M2 Macrophage infiltration in AA TNBCs by using large-scale and diverse clinical cohorts of TNBCs derived from distinct AA and EA populations within the U.S. Additionally, we will test for the association of MYC-MIZ1 signaling and immune infiltration modulation with patient prognosis, clinicopathologic and/or lifestyle factors. Our studies will identify mechanisms contributing to chemotherapy resistance and racial disparities in TNBC outcomes, enabling development of prognostic biomarkers and targeted therapeutic strategies.

项目摘要 三阴性乳腺癌 (TNBC) 是乳腺癌的一种异质亚型，治疗方法有限 且经常表现出对化疗的耐药性，导致 TNBC 患者预后较差。 美国非裔美国 (AA) 女性 TNBC 发病率较高且临床状况较差 与欧洲美国 (EA) 同行相比的结果。这些与种族相关的差异 在控制社会经济和治疗差异后，结果仍然显着，表明 AA 与 EA TNBC 之间存在肿瘤生物学的内在差异，并导致结果差异。 为了解码导致 TNBC 负担不平等的生物因素，我们采用了一种新颖的系统 生物学方法 (InFlo) 询问 AA 和 EA 女性中 TNBC 的转录组图谱，并确定 MYC-MIZ1 信号在高达 70% 的 AA TNBC 中被不同程度地激活，而 EA 中只有 30% 被激活 TNBC。携带 MYC-MIZ1 激活的 TNBC 的患者表现出较差的总体生存率。此外，我们 发现与 EA 相比，AA 中 TNBC 的 M2 巨噬细胞浸润水平更高（>2 倍），这表明 致瘤免疫微环境导致 AA 中不同的癌症负担。这些发现 首次表明，MYC-MIZ1 信号传导和炎症的种族相关差异 免疫调节共同导致 TNBC 结果差异。制定本提案是为了描述 MYC-MIZ1 信号传导和 M2 巨噬细胞在 TNBC 差异中的生物学作用如下： 目标 1：使用在 AA 和 EA 原代 TNBC 组织和细胞系模型中进行的多组学评估来 破译 TNBC 中 MYC-MIZ1 信号传导的上游调节因子和下游调节因子。我们将 使用 co- 解码 TNBC 中肿瘤 MYC-MIZ1 信号传导和 M2 巨噬细胞浸润之间的串扰 培养实验。这些研究将首次建立 MYC-MIZ1 信号传导的监管路线图 TNBC 中的免疫微环境和免疫微环境之间的功能串扰机制 AA 与 EA TNBC 中的肿瘤 MYC-MIZ1 信号传导。目标 2：确定 MYC-MIZ1 信号传导是否 利用临床前细胞系的基因操作研究调节 TNBC 对化疗的反应， 异种移植和 PDX 模型系统。这些研究将揭示 MYC-MIZ1 信号在 赋予 TNBC 化疗耐药性，并揭示该领域潜在的新治疗策略 疾病。目标 3：评估频繁 MYC-MIZ1 信号激活和 M2 增加的普遍性 通过使用源自 AA TNBC 的大规模且多样化的 TNBC 临床队列，进行巨噬细胞浸润 美国境内不同的 AA 和 EA 人群此外，我们将测试 MYC-MIZ1 的关联 信号传导和免疫浸润调节与患者预后、临床病理和/或生活方式因素的关系。 我们的研究将确定导致 TNBC 化疗耐药和种族差异的机制 结果，从而能够开发预后生物标志物和有针对性的治疗策略。