Aneuploidy selects for the acquisition of driver genes in breast cancer

Key Points:

• Basal-like breast cancer (BLBC) shows distinct chromosome arm-level copy number alterations (CNAs) with high specificity and prevalence, identified through TCGA and METABRIC datasets; key gains and losses correlate strongly with BLBC subtype compared to others.
• Integrated single-cell RNA sequencing and PAM50 subtyping reveal that basal-like tumors have significantly higher genomic instability and specific arm-level CNAs, which are predominantly clonal within this subtype.
• CRISPR-KOALA functional screens in mouse models demonstrate that knockout or activation of driver genes on recurrently altered chromosome arms accelerates tumor onset and influences tumor morphology, confirming their role in BLBC pathogenesis.
• Overexpression of the PLGRKT gene promotes mammary tumor development and cutaneous squamous cell carcinoma in mice, with mitochondrial localization and increased oxidative phosphorylation, suggesting a role in tumor metabolism and progression.
• Functional studies reveal that PLGRKT overexpression enhances mitochondrial respiration without altering substrate oxidation and confers resistance to oxidative stress and certain chemotherapeutics, highlighting its potential as a therapeutic target in BLBC.