The Role of Kaiso as a predictive breast cancer biomarker in Africa and across the African Diaspora

Kaiso 作为非洲和整个非洲侨民的乳腺癌预测生物标志物的作用

基本信息

批准号：
10347874
负责人：
KEVIN L. GARDNER
金额：
$ 64.96万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10347874
关键词：
4T1 Admixture Africa African African Caribbean African ancestry Alcohols Beds Behavior Biological Breast Adenocarcinoma Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Breast Feeding Cell Line Cell Nucleus Cells Collaborations Country Cytoplasm Data Engineering Environmental Exposure Epidemiologist Ethnic Origin Ethnic group European Evolution Frequencies Gene Expression Gene Expression Profile Genes Genetic Genome Genomics Goals Growth Herbert Irving Comprehensive Cancer Center Heterogeneity High Prevalence Immune Immune Evasion Immune response Immunofluorescence Immunologic Immunohistochemistry Inbred BALB C Mice Institutional Racism Kenya Life Style Link Malignant Neoplasms Modeling Molecular Mus Mutation Neoadjuvant Therapy Neoplasm Metastasis New York Nigeria North Carolina Nuclear Outcome Pathologist Patients Pattern Pharmacology Population Predictive Value Process Property Race Reproductive History Research Personnel Role Somatic Mutation The Cancer Genome Atlas Tissue Microarray Tissues Tobacco Tumor Biology Tumor-Derived United States Universities University Hospitals Variant Washington Woman Xenograft Model aggressive breast cancer base breast cancer survival cancer biomarkers cancer health disparity cancer subtypes cellular engineering cohort efficacy testing exhaust exome sequencing extracellular vesicles genetic signature health care availability high risk improved malignant breast neoplasm multidisciplinary multiple omics non-genetic pathogen exposure patient stratification population genetic structure predicting response predictive marker prognostic model prognostic value protein biomarkers racial and ethnic racial diversity response socioeconomic disadvantage survival prediction therapy resistant transcriptome sequencing treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Around the world, women of African ancestry and throughout the African Diaspora, continue to perish from breast cancer at significantly higher rates than any other racial/ethnic group. Although much of these disparate outcomes have been attributed to inequities in access to healthcare, socioeconomic disadvantage, and other crippling exposures linked to institutional racism, most studies also indicate a prominent role in tumor biology. Causal factors include i) higher frequencies of aggressive breast cancer subtypes associated with genetic ancestry; ii) more aggressive biological behavior of low-risk breast cancers based-on race/ethnicity and ancestry, and iii) decreased predictive value of prognostic gene signatures when applied to women of African heritage. Recently we have shown the subcellular localization of the breast cancer biomarker Kaiso (ZBTB33) in both the nucleus and cytoplasm of breast cancer cells were each more associated with biologically aggressive cancers and independent predictors of poor breast cancer survival and response to neoadjuvant therapy, revealing that cytoplasmic Kaiso was highly correlated with an “immune-evasive” or “immune-suppressed” tumor microenvironment. Mechanistically cytoplasmic Kaiso was shown to be very highly correlated with the machinery involved in extracellular vesicle (EV) loading and secretion, a process known to have a dramatic influence on the micro-environment of the tumor bed and metastatic niche. In this study, we will validate and extend these observations of the subcellular localization of Kaiso as an independent predictive biomarker of breast cancer survival and the tumor micro-environment using two diverse breast cancer cohorts from Africa and across the African diaspora. One from the Columbia University Herbert Irving Comprehensive Cancer Center (N=487) and the other from the Aga Khan University Hospital, Nairobi, Kenya (N=237) (Specific Aim 1). Using a multi-omic approach that will integrate the analysis of tissue microarrays (TMAs), quantitative multiplex immunofluorescence (qMIF), gene expression (RNA-seq), tumor mutational signatures and frequency (whole- exome sequencing), deep annotation of patient clinicopathological features, environmental exposures, and genetic ancestry, we will define prognostic models that will demonstrate the role of Kaiso in predicting breast cancer survival, response to therapy and the role of genetic ancestry in breast cancer evolution and outcome (Specific Aim 1). We will also define how Kaiso modulates the influence of EV secretion on breast cancer growth, invasion, metastasis, and immune evasion in murine xenograft models using cells engineered for depleted or enhanced Kaiso expression (Specific Aim 2). These goals will be accomplished through a transatlantic collaboration of a highly-specialized multi-disciplinary team of breast cancer pathologists, tumor biologists, molecular biologists, biostatisticians, bioinformaticians, epidemiologists, genome researchers, and cancer health disparities investigators.

在世界各地，非洲血统的妇女和整个非洲侨民继续死于乳腺癌癌症的发病率明显高于任何其他种族/族裔群体，尽管其中许多是不同的。结果被归因于获得医疗保健的不平等、社会劣势和其他大多数研究还表明，与制度性种族主义有关的严重暴露在肿瘤生物学中发挥着重要作用。致病因素包括 i) 与遗传相关的侵袭性乳腺癌亚型的发生率较高血统；ii) 基于种族/民族和血统的低风险乳腺癌更具侵袭性的生物学行为， iii) 当应用于非洲裔女性时，预后基因特征的预测价值降低。最近，我们展示了乳腺癌生物标志物 Kaiso (ZBTB33) 在两种细胞中的亚细胞定位。乳腺癌细胞的细胞核和细胞质与生物侵袭性癌症的相关性更高以及乳腺癌生存不良和新辅助治疗反应的独立预测因素，揭示了细胞质 Kaiso 与“免疫逃避”或“免疫抑制”肿瘤高度相关从机制上讲，细胞质 Kaiso 与机制高度相关。参与细胞外囊泡 (EV) 的装载和分泌，这一过程已知对在本研究中，我们将验证并扩展肿瘤床的微环境和转移生态位。 Kaiso 作为乳腺癌独立预测生物标志物的亚细胞定位观察使用来自非洲和整个世界的两个不同乳腺癌队列研究生存和肿瘤微环境非洲侨民。一名来自哥伦比亚大学赫伯特·欧文综合癌症中心 (N=487) 和另一个来自肯尼亚内罗毕阿迦汗大学医院 (N=237)（具体目标 1）。整合组织微阵列 (TMA) 分析、定量多重分析的方法免疫荧光（qMIF）、基因表达（RNA-seq）、肿瘤突变特征和频率（全外显子组测序）、患者临床病理特征、环境暴露的深度注释，以及遗传血统，我们将定义预后模型，证明 Kaiso 在预测乳腺癌方面的作用癌症生存、对治疗的反应以及遗传血统在乳腺癌演变和结果中的作用（具体目标 1）我们还将定义 Kaiso 如何调节 EV 分泌对乳腺癌生长的影响，使用经过改造的细胞进行小鼠异种移植模型中的侵袭、转移和免疫逃避增强 Kaiso 的表达（具体目标 2）。这些目标将通过跨大西洋来实现。由乳腺癌病理学家、肿瘤生物学家、分子生物学家、生物统计学家、生物信息学家、流行病学家、基因组研究人员和癌症健康差异调查员。