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

> **NIH NIH P20** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $218,709

## Abstract

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...

## Key facts

- **NIH application ID:** 10469706
- **Project number:** 3P20CA233216-03S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Vinay Varadan
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $218,709
- **Award type:** 3
- **Project period:** 2018-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469706

## Citation

> US National Institutes of Health, RePORTER application 10469706, Role of MYC-MIZ1 signaling and the inflammatory immune microenvironment in Triple-Negative Breast Cancer Racial Disparities (3P20CA233216-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10469706. Licensed CC0.

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