Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Genetics
• Bioinformatics

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 expression, presenting significant challenges in treatment and understanding its molecular drivers.
• Tumor heterogeneity and therapy resistance in TNBC are poorly understood, necessitating research into the underlying molecular mechanisms, particularly those related to cancer stemness.

Purpose of the Study:

• To identify stemness-associated genes contributing to triple-negative breast cancer (TNBC) progression and malignant phenotypes.
• To investigate the correlation of identified gene signatures with tumor hypoxia, stemness markers, and the tumor immune microenvironment in TNBC.

Main Methods:

• Bioinformatic analysis was employed to identify differentially expressed genes in TNBC.
• Parametric Gene Set Enrichment Analysis (PGSEA) was used to assess gene set enrichment and correlations.
• Experimental validation involved assessing gene expression changes upon depletion of nucleus accumbens-associated protein 1 (NAC1).

Main Results:

• A signature of five upregulated genes (CDK1, EZH2, CCNB1, CCNA2, AURKA) associated with cell regeneration was identified in TNBC.
• This five-gene signature positively correlated with tumor hypoxia and stemness-associated gene clusters.
• Increased infiltration of immunosuppressive cells was also positively correlated with the expression of these five genes, and NAC1 depletion reduced their expression.

Conclusions:

• The identified five-gene signature (CDK1, EZH2, CCNB1, CCNA2, AURKA) may serve as a potential biomarker for TNBC heterogeneity and stemness.
• This signature is associated with a tumor microenvironment characterized by high hypoxia, stemness enrichment, and immune suppression.
• Further research into this gene signature could lead to novel therapeutic strategies for TNBC.