TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Genomic aberrations are challenging to study in epithelial cell immortalization due to a lack of isogenic models.
• Identifying early molecular events is crucial for understanding cancer initiation.

Purpose of the Study:

• To identify transcriptomic changes associated with epithelial cell immortalization.
• To investigate the role of Tonsoku-like (TONSL) in breast cancer development and its therapeutic potential.

Main Methods:

• Utilized healthy primary breast luminal epithelial cells and their hTERT-immortalized counterparts.
• Analyzed breast tumor microarrays and performed in vivo studies in mice.
• Investigated TONSL's effect on chromatin accessibility, gene expression, and DNA repair pathways.

Main Results:

• Elevated TONSL expression was an early event in cell immortalization and is amplified in ~20% of breast cancers.
• TONSL alone immortalized cells and, with oncogenes, induced tumors in mice, correlating with poor patient survival.
• TONSL modulated transcription factor access, enhanced homologous recombination DNA repair, and was essential for tumor growth in vivo.

Conclusions:

• TONSL is a key regulator of epithelial cell immortalization and facilitates breast cancer initiation.
• TONSL represents a promising therapeutic target for breast cancer, with inhibitors showing efficacy.