# Deciphering the function of DNp63 and MDSCs in tumor promotion and metastasis of TNBCs

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $373,520

## Abstract

Project Summary
Breast cancer remains a major health threat and is the second leading cause of cancer-related death in
women in the United States. Treatment of triple negative breast cancer (TNBC) patients is particularly
challenging due to the heterogeneity of the disease and plasticity of the cancer cells. TNBC represents about
15% of all breast cancers and is a particularly aggressive subtype, with limited treatment options and very poor
prognosis. The plasticity and heterogeneity of TNBCs makes them difficult to target therapeutically. Mounting
evidence suggests that normal cells within the tumor microenvironment (TME) play an important role in
dictating tumor cell fate. Compared to the unstable genome of cancer cells, the stable genomes of normal cells
within the TME make them ideal targets for drug therapies that can be used in combination with therapies
targeting cancer cells. Immune cells within the TME play an essential role in tumor progression and
metastasis. Moreover, increased numbers of one subtype of immune cell, myeloid-derived suppressor cells
(MDSCs), in circulating blood correlates with clinical stage, metastatic tumor burden and increased numbers of
circulating tumor cells (CTCs), suggesting it may be a promising prognostic marker in breast cancer patients.
However, it is currently unclear if MDSCs are recruited to the TME of TNBC and/or if they contribute to tumor
progression and metastasis. Using human patient samples, we found increased numbers of MDSCs in TNBC
patient tumors compared to other breast cancer subtypes. Moreover, we found increased expression of Np63
in TNBC patient samples with a high degree of MDSC infiltration, raising the intriguing possibility that MDSC
recruitment and/or survival may be driven by Np63 expression in TNBC patients. In support, our published
and preliminary studies demonstrate that reducing the level of Np63 in TNBCs decreases tumor growth,
progression and metastasis and is associated with reduced MDSC infiltrate. Additionally, we showed reduction
of chemokine and Tumor necrosis Factor (TNF) pathway genes in Np63-KD TNBC cells compared to control
cells, thus identifying a potential pathways by which Np63+ TNBC cells may regulate chemokine-dependent
recruitment and TNF-mediated survival of MDSCs in TNBCs. Finally, we show that MDSCs can promote
cancer stem cell function of TNBC cells. Together, our data indicates a novel crosstalk between Np63+ TNBC
cells and MDSCs in TNBCs, which could promote the aggressive nature of TNBC tumors, thereby increasing
metastasis and mortality of patients. Based on these data, the goal of the current proposal is to delineate
a novel mechanism by which Np63+ TNBC cells mediated chemokine and TNF signaling promotes
MDSC infiltration and survival, which then feeds back to TNBC cells to promote cancer progression
and metastasis.

## Key facts

- **NIH application ID:** 9934151
- **Project number:** 5R01CA237243-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Rumela Chakrabarti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,520
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934151

## Citation

> US National Institutes of Health, RePORTER application 9934151, Deciphering the function of DNp63 and MDSCs in tumor promotion and metastasis of TNBCs (5R01CA237243-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934151. Licensed CC0.

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