The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair

Area of Science:

• Molecular Biology
• Genetics
• Oncology

Background:

• The acetyltransferase Tip60/Kat5 is involved in diverse biological processes, including acetylation of histone and non-histone proteins.
• Tip60's role as a tumor suppressor is suggested by its control of p53-dependent transcription, but its function independent of p53 is less understood.

Purpose of the Study:

• To investigate the tumor suppressor role of Tip60 in breast cancer, particularly its function independent of p53.
• To determine the impact of Tip60 loss on DNA repair mechanisms and mammary tumorigenesis.

Main Methods:

• Utilized a p53-null mouse model of invasive breast adenocarcinoma.
• Assessed DNA repair capacity in mammary epithelial cells with varying Tip60 levels under normal and genotoxic stress conditions.
• Analyzed gene expression signatures related to homologous recombination (HR) DNA repair.
• Examined Tip60 mRNA levels and p53 mutation status in human breast cancer datasets.

Main Results:

• Heterozygosity for Tip60 deletion accelerated mammary tumorigenesis in a p53-null mouse model.
• Reduced Tip60 levels impaired DNA repair in mammary epithelial cells, both resting and stressed.
• Tip60 was shown to regulate homologous recombination (HR)-directed DNA repair.
• Low Tip60 mRNA levels correlated with defective HR gene expression signatures and p53 mutations in human breast cancers.

Conclusions:

• Tip60 functions as a novel breast tumor suppressor gene.
• Loss of Tip60 leads to genomic instability by compromising DNA repair, specifically HR.
• These findings highlight Tip60 as a potential therapeutic target in breast cancer, particularly in cases with p53 mutations.