ΔNp63 regulates MDSC survival and metabolism in triple-negative breast cancer

Ukjin Kim; Rahul Debnath; Javier E Maiz; Joshua Rico; Satrajit Sinha; Mario Andrés Blanco; Rumela Chakrabarti

doi:10.1016/j.isci.2024.109366

ΔNp63 regulates MDSC survival and metabolism in triple-negative breast cancer

iScience. 2024 Feb 29;27(4):109366. doi: 10.1016/j.isci.2024.109366. eCollection 2024 Apr 19.

Authors

Ukjin Kim¹, Rahul Debnath², Javier E Maiz¹, Joshua Rico², Satrajit Sinha³, Mario Andrés Blanco², Rumela Chakrabarti^{1

2}

Affiliations

¹ Department of Surgery, Sylvester Comprehensive Cancer, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
² Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.

Abstract

Triple-negative breast cancer (TNBC) contributes greatly to mortality of breast cancer, demanding new targetable options. We have shown that TNBC patients have high ΔNp63 expression in tumors. However, the function of ΔNp63 in established TNBC is yet to be explored. In current studies, targeting ΔNp63 with inducible CRISPR knockout and Histone deacetylase inhibitor Quisinostat showed that ΔNp63 is important for tumor progression and metastasis in established tumors by promoting myeloid-derived suppressor cell (MDSC) survival through tumor necrosis factor alpha. Decreasing ΔNp63 levels are associated with decreased CD4⁺ and FOXP3⁺ T-cells but increased CD8⁺ T-cells. RNA sequencing analysis indicates that loss of ΔNp63 alters multiple MDSC properties such as lipid metabolism, chemotaxis, migration, and neutrophil degranulation besides survival. We further demonstrated that targeting ΔNp63 sensitizes chemotherapy. Overall, we showed that ΔNp63 reprograms the MDSC-mediated immunosuppressive functions in TNBC, highlighting the benefit of targeting ΔNp63 in chemotherapy-resistant TNBC.

Keywords: Biochemistry; Biological sciences; Cancer; Cancer systems biology; Cell biology; Health sciences; Internal medicine; Medical specialty; Medicine; Natural sciences; Oncology; Systems biology.