# Unravel the novel role of S100A7 and its functional partners in Metastatic Triple Negative Breast Cancer Racial Disparity

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $469,544

## Abstract

Triple-negative breast cancer (TNBC) disproportionately affects African American (AA) women, with mortality
rates 65% higher than Caucasian (CA) women. The mechanisms underlying the heightened aggressiveness
and metastasis in AA TNBC remain elusive. This study investigates the immune suppressive tumor
microenvironment (TME) as a driving factor in AA TNBC progression. Specifically, it delves into the novel role
of the S100A7 and its interplay with intrinsic IFNγ signaling, elucidating their impact on TNBC aggressiveness
and metastasis in AA women. Our recent findings reveal elevated S100A7 expression in AA TNBC patient
samples and cell lines relative to CA counterparts. Moreover, higher S100A7 expression correlates with
increased tumor burden in various pre-clinical models, including AA TNBC patient-derived xenografts (PDX).
We also noted that S100A7 knockout (KO) mouse models (generated in our lab) exhibit reduced tumor burden,
while treatment with a novel S100A7-neutralizing antibody (nAb) shows promising efficacy in inhibiting TNBC
growth and metastasis. Mechanistically, S100A7 is demonstrated to enhance cPLA2/PGE2/IFNGR1 signaling
in AA TNBC cells, modulating intrinsic IFNγ signaling. This process generates an immune suppressive TME by
upregulating PD-L1 and downregulating Fas on tumor cells. Additionally, AA TNBC tumor tissues manifest
heightened immunosuppression, characterized by increased PD-L1 expression and infiltration of FoxP3+ Treg
cells. Our proposed research aims to meticulously uncover how S100A7 orchestrates IFNγ responsive genes
(PD-L1 and Fas) to generate an immunosuppressive TME in AA TNBC. This investigation leverages diverse
AA TNBC cell lines, humanized PDX models, and genetically engineered mouse models (GEMMs)
overexpressing mS100a7, mS100a7 KO, and the S100A7 nAb. The study's overarching hypothesis posits
that S100A7 contributes to AA TNBC aggressiveness by fostering an immunosuppressive and immune evasive
TME via regulating intrinsic IFNγ signaling, resulting in PD-L1 upregulation and Fas downregulation. The
research strategy encompasses three key aims: Aim 1 will elucidate how S100A7 signaling regulates IFNγ
responsive genes in AA TNBC using AA TNBC cells and mS100a7 GEMMs. Aim 2 will determine the novel
role of S100A7 in regulating macrophage plasticity, T cell function, and Fas-mediated immune evasion in AA
TNBC. Aim 3 will evaluate the therapeutic efficacy of S100A7 nAb in combination with chemo or
immunotherapy using AA TNBC PDOs and PDX mouse models. This aim will also determine the prognostic
significance of S100A7 and its downstream signaling molecules in AA TNBC. In addition, this aim will establish
the association of S100A7 and various immune cells in TNBC racial disparity. The insights gained are poised
to identify novel S100A7-mediated downstream signaling pathways and determine the clinical relevance of
S100A7 in AA TNBC. This study holds the immense potential to inform the design of innovative therapeutic
s...

## Key facts

- **NIH application ID:** 10946343
- **Project number:** 1R01CA292020-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Ramesh K. Ganju
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $469,544
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946343

## Citation

> US National Institutes of Health, RePORTER application 10946343, Unravel the novel role of S100A7 and its functional partners in Metastatic Triple Negative Breast Cancer Racial Disparity (1R01CA292020-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10946343. Licensed CC0.

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