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

项目摘要 三阴性乳腺癌(TNBC)是乳腺癌的一种异质性亚型，治疗有限。 而且经常表现出对化疗的耐药性，导致TNBC患者预后较差。 美国非裔美国人(AA)女性的TNBCs发病率较高，临床表现较差 结果与欧洲美洲(EA)同行相比。这些与种族相关的差异 在控制了社会经济和治疗差异后，结果仍然显著，这表明 AA和EA TNBCs之间存在肿瘤生物学上的内在差异，这是导致结果差异的原因之一。 为了破译导致TNBC负担不均匀的生物因素，我们采用了一种新的系统 生物学方法(INFLO)询问AA和EA妇女TNBCs的转录组谱，并确定 MYC-MIZ1信号在高达70%的AA TNBC中被完全不同地激活，而在EA中只有30% TNBCS。携带MYC-MIZ1激活的TNBCs的患者总体存活率较低。此外，我们 与EA相比，AA患者TNBCs中M2巨噬细胞的浸润水平更高(&gt；2倍)，这表明 致瘤免疫微环境导致了AAS中不同的癌症负担。这些发现 首次提出，MYC-MIZ1信号和炎症的种族相关差异 免疫调节共同导致了TNBC结果的差异。这项提议是为了划定 MYC-MIZ1信号和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执行的多组学评估 破译TNBCs中MYC-MIZ1信号的上游调节因子和下游调节因子。我们会 联合检测肿瘤MYC-MIZ1信号和M2巨噬细胞在TNBCs中的表达 培养实验。这些研究将首次建立MYC-MIZ1信号的调控路线图 以及免疫微环境和TNBCs之间的功能串扰的潜在机制 AA和EA TNBCs中的肿瘤MYC-MIZ1信号转导。目标2：确定MYC-MIZ1信号 在临床前细胞系中利用基因操作研究调节TNBC对化疗的反应， 异种移植和PDX模型系统。这些研究将揭开MYC-MIZ1信号在体内的功能作用。 TNBCs的化疗耐药性，并揭示了潜在的新的治疗策略 疾病。目的3：评估MYC-MIZ1信号频繁激活和M2增加的共性 再生障碍性贫血TNBCs中巨噬细胞的侵袭 美国不同的AA和EA人群。此外，我们将测试MYC-MIZ1的关联性 信号和免疫渗透与患者预后、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，能够开发预后生物标记物和有针对性的治疗策略。

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.