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Principal Investigator: KEVIN L. GARDNER
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $569,880
Funding agency: National Cancer Institute
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.
Terms: <4T1><Admixture><Africa><African><African Caribbean><African Females><African Women><African ancestry><African descent><Afro-Caribbean><Alcohol Chemical Class><Alcohols><BALB C Mouse><BALB/c><Beds><Behavior><Biological><Body Tissues><Breast Adenocarcinoma><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Cancer Risk Factor><Breast Feeding><Breast Tumor Patient><Breast fed><Breastfed><Breastfeeding><Cancers><Cell Body><Cell Line><Cell Nucleus><CellLine><Cells><Collaborations><Country><Cytoplasm><Data><Engineering><Environmental Exposure><Epidemiologist><Ethnic Group><Ethnic Origin><Ethnic People><Ethnic Population><Ethnic individual><Ethnicity><Ethnicity People><Ethnicity Population><European ancestry><Evolution><Expression Signature><Frequencies><Gene Expression><Gene Expression Profile><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Genomics><Goals><Growth><Height><Herbert Irving Comprehensive Cancer Center><Heterogeneity><High Prevalence><Immune><Immune Evasion><Immune response><Immunes><Immunofluorescence><Immunofluorescence Immunologic><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Inbred BALB C Mice><Induction Therapy><Institutional Racism><Invaded><Investigators><Kenya><Life Style><Lifestyle><Link><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mammary adenocarcinoma><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Mutation><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Metastasis><New York><Nigeria><North Carolina><Nuclear><Nucleus><Outcome><Pathologist><Patients><Pattern><Population><Prediction of Response to Therapy><Predictive Value><Process><Property><RNA Seq><RNA sequencing><RNAseq><Race><Races><Racial Group><Reproductive Factors><Reproductive History><Reproductive History Epidemiology><Reproductive Issues><Research Personnel><Researchers><Role><Secondary Neoplasm><Secondary Tumor><Shapes><Socioeconomically disadvantaged><Somatic Mutation><Strains Cell Lines><Systematic Racism><Systemic Racism><TCGA><TNBC><The Cancer Genome Atlas><Tissue Arrays><Tissue Chip><Tissue Growth><Tissue Microarray><Tissues><Tobacco><Tumor Biology><Tumor-Derived><United States><Universities><University Hospitals><Variant><Variation><Washington><Woman><Xenograft Model><access disparities><access to health care><access to healthcare><accessibility disparities><accessibility of health care><accessibility to health care><accessibility to healthcare><aggressive breast cancer><biologic><black Caribbean><black carib><breast cancer risk><breast cancer survival><breast tumor cell><cancer biomarkers><cancer disparity><cancer health disparity><cancer markers><cancer metastasis><cancer microenvironment><cancer progression><cancer sub-types><cancer subtypes><cancer-related health disparity><cell engineering><cellular engineering><cohort><cultured cell line><disparate effect><disparate impact><disparate result><disparities in access><disparity in cancer><efficacy testing><ethnic subgroup><ethnicity group><exhaust><exome sequencing><exome-seq><extracellular vesicles><gene expression pattern><gene expression signature><gene signatures><genetic signature><genome mutation><health care access><health care availability><health care service access><health care service availability><healthcare access><healthcare accessibility><healthcare availability><healthcare service access><healthcare service availability><high risk><host response><immune evasive><immune microenvironment><immune system response><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><induction therapies><inequality in access><inequitable effect><inequitable impact><inequitable outcome><inequity in access><inequity in accessibility><malignancy><malignant breast tumor><multidisciplinary><multiomics><multiple omics><neoplasm progression><neoplasm/cancer><neoplastic progression><non-genetic><nongenetic><ontogeny><outcome disparities><outcome inequality><outcome inequity><overexpress><overexpression><panomics><pathogen exposure><patient stratification><pharmacologic><population genetic structure><predict therapeutic response><predict therapy response><predictive biomarkers><predictive marker><predictive molecular biomarker><prognosis model><prognostic ability><prognostic model><prognostic power><prognostic utility><prognostic value><protein biomarkers><protein markers><racial><racial background><racial diversity><racial origin><racial population><racial subgroup><racially diverse><resistance to therapy><resistant to therapy><response><response to therapy><response to treatment><social role><socio-economic disadvantage><socio-economically disadvantaged><socio-economically underprivileged><socioeconomic disadvantage><socioeconomically underprivileged><somatic variant><stratified patient><survival prediction><therapeutic resistance><therapeutic response><therapy prediction><therapy resistant><therapy response><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treatment prediction><treatment resistance><treatment response><treatment response prediction><treatment responsiveness><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor progression><tumor-immune system interactions><unequal effect><unequal impact><unequal outcome><xenograft transplant model><xenotransplant model>