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）是一种异质性乳腺癌亚型，治疗有限 在TNBC患者中，化疗是一种选择，并且经常表现出对化疗的抗性，导致预后较差。 美国的非洲裔美国人（AA）女性患有较高的TNBC发病率和较差的临床表现。 与欧美（EA）同行相比。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，这表明 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。 为了解码造成不平等TNBC负担的生物因素，我们采用了一种新的系统， 生物学方法（InFlo）来询问AA和EA女性中TNBC的转录组谱，并确定了 MYC-MIZ 1信号在高达70%的AA TNBC中被激活，而EA仅为30% 跨国公司。携带MYC-MIZ 1活化的TNBC的患者表现出较差的总体存活率。而且我们 发现与EA相比，AA中TNBC中M2巨噬细胞浸润水平更高（>2倍），表明 致瘤性免疫微环境导致AA中不同的癌症负荷。这些发现 这首次表明，MYC-MIZ 1信号传导和炎症反应的种族相关差异， 免疫调节共同促成TNBC结果差异。该提案旨在描绘 MYC-MIZ 1信号传导和M2巨噬细胞在TNBC差异中的生物学作用如下： 目的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， 破译TNBC中MYC-MIZ 1信号传导的上游调节因子和下游介导因子。我们将 使用共表达技术解码肿瘤MYC-MIZ 1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-MIZ 1信号转导调控路线图的研究。 以及免疫微环境和免疫细胞之间的功能串扰的潜在机制。 AA与EA TNBC中的肿瘤MYC-MIZ 1信号传导。目的2：确定MYC-MIZ 1信号传导是否 在临床前细胞系中使用遗传操作研究调节TNBC对化疗的反应， 异种移植物和PDX模型系统。这些研究将揭示MYC-MIZ 1信号在细胞内的功能作用。 赋予TNBC化疗耐药性，并揭示了这一领域潜在的新治疗策略。 疾病目的3：评估频繁MYC-MIZ 1信号传导激活和M2增加的普遍性 通过使用来自于以下的大规模和多样化的TNBC临床队列， 此外，我们将测试MYC-MIZ 1与AA和EA之间的关联。 信号传导和免疫浸润调节与患者预后、临床病理学和/或生活方式因素有关。 我们的研究将确定导致TNBC化疗耐药性和种族差异的机制 结果，使预后生物标志物和有针对性的治疗策略的发展。

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.