Author ORCID Identifier
https://orcid.org/0009-0005-4838-0684
Date Available
4-8-2024
Year of Publication
2024
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
First Advisor
JIN-MING YANG
Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous and the most lethal breast cancer (BC) subtype. We report here a new role of nucleus accumbens associated protein 1 (NAC1) in maintaining stemness signature and features of TNBC and controlling the status of myeloid-derived suppressor cells, which accounts for its role in tumor progression and metastasis. This report demonstrates increased NAC1 amplification in TNBC metastatic samples compared to nonmetastatic tissues. In vitro, NAC1 depletion in TNBC cells suppressed their proliferation, colony formation, migration, and invasion. In vivo, NAC1 knockdown in TNBC cells reduced tumorigenic ability, diminished tumor growth rate, and abolished metastasis in NK cell-competent mice. Conversely, depletion of tumoral NAC1 promoted tumor growth and increased metastasis in NK cell-deficient mice. Depletion of NK cells or myeloid-derived cells in mice xenografted with NAC1 knockdown cells rescued the lost tumor initiation abilities and promoted tumor growth. Moreover, NAC1-/- CD11b+/Gr1+cells, which mark murine myeloid immune suppressive cells, decrease the number of CSCs and inhibit tumor cell proliferation in co-culture. NAC1 depletion in tumor cells, followed by RNA sequencing and bioinformatics analysis on stemness signatures regulated by NAC1, demonstrated the multifaceted role of NAC1 in TNBC progression. Mechanistically, NAC1 transcriptionally upregulates JAK1, which phosphorylates STAT3, leading to increased IL6, G-CSF, and other tumor microenvironment-regulating cytokines to enhance CSCs and immune interactions. The results presented here highlight the importance of NAC1 as a target in unraveling the TNBC stemness-immunosuppressive niche to improve therapeutic response.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.227
Recommended Citation
ngule, chrispus, "THE CRITICAL ROLE OF NAC1 IN TRIPLE-NEGATIVE BREAST CANCER STEMNESS AND IMMUNOSUPPRESSION" (2024). Theses and Dissertations--Toxicology and Cancer Biology. 55.
https://uknowledge.uky.edu/toxicology_etds/55
