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: 10005930
• 负责人: Vinay Varadan
• 金额: $ 34.08万
• 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/10005930
• 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; Chronic; Clinical; Clinical Management; Clinical Trials; Coculture Techniques; Comprehensive Cancer Center; DNA Methylation; Data; Data Set; Databases; Development; Disease; Disease model; Encyclopedias; Ethnic Origin; 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; 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 therapeutics; outcome forecast; 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）是乳腺癌的异质亚型，治疗有限 选择和经常表现出对化疗的抗性，导致TNBC患者的预后较差。 美国的非裔美国人（AA）妇女患有TNBC的发病率和较差的临床发病率较高 与他们的欧美（EA）同行相比，结果。这些与种族相关的差异 在控制社会经济和治疗差异之后，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。 为了解释导致不平等TNBC负担的生物学因素，我们采用了一种新型系统 生物学方法（INFLO）询问AA和EA妇女中TNBC的转录组轮廓，并确定 MYC-MIZ1信号传导在多达70％的AA TNBC中被不同激活，而EA的30％仅为30％ TNBC。拥有MYC-MIZ1激活的TNBC的患者的总生存率较差。此外，我们 与EA相比 肿瘤性免疫微环境有助于AAS中不同的癌症负担。这些发现 首次提出与种族相关的MYC-MIZ1信号传导和炎症的差异 免疫调节共同导致TNBC结果差异。该建议是为了描绘 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： AIM 1：使用在AA和EA主要TNBC组织和细胞系模型中进行的多摩学评估 TNBC中MYC-MIZ1信号传导的上游调节器和下游介体。我们将 使用共同的TNBC中的肿瘤MYC-MIZ1信号传导和M2巨噬细胞浸润之间的串扰 培养实验。这些研究将是第一个建立MYC-MIZ1信号的法规路线图的研究 在TNBC和免疫微环境和 AA与EA TNBC中的肿瘤MYC-MIZ1信号传导。 AIM 2：确定MYC-MIZ1是否信号传导 使用临床前细胞系中的遗传操纵研究调节TNBC对化学疗法的反应， 异种移植和PDX模型系统。这些研究将揭示Myc-Miz1信号在中的功能作用 在TNBC中提供化学疗法抗性，并在此揭示潜在的新型治疗策略 疾病。 AIM 3：评估频繁的Myc-Miz1信号激活的通用性并增加了M2 通过使用源自源自的大规模和多样化的TNBC，AA TNBC中的巨噬细胞浸润 在美国境内的不同AA和EA人群，我们还将测试Myc-Miz1的关联 患者预后，临床病理和/或生活方式因素，信号传导和免疫浸润调节。 我们的研究将确定导致TNBC化学疗法抗性和种族差异的机制 结果，可以发展预后生物标志物和有针对性的治疗策略。