Disrupting PHF8-TOPBP1 connection elicits a breast tumor-specific vulnerability to chemotherapeutics

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• The DNA damage response (DDR) pathway is crucial for maintaining genome stability.
• Defects in DDR are therapeutically exploited in cancer treatment.
• PHF8's role in demethylating TOPBP1 and activating ATR kinase in replication stress response is known, but its link to tumorigenesis is unclear.

Purpose of the Study:

• To investigate the role of PHF8-mediated TOPBP1 demethylation in breast tumorigenesis.
• To determine the clinical association of PHF8 dysregulation with breast cancer.
• To explore therapeutic strategies targeting the PHF8-TOPBP1 axis.

Main Methods:

• Analysis of clinical breast tumor samples and patient survival data.
• Generation and study of Phf8 knockout mouse models.
• CRISPR/Cas9 mutation modeling in breast tumor cells.
• Assessment of ATR kinase activity, TOPBP1 methylation status, and chromosomal instability.

Main Results:

• PHF8-promoted TOPBP1 demethylation is clinically linked to breast tumorigenesis and patient survival.
• Phf8 knockout mice develop slow-growing mammary tumors with increased chromosomal instability and reduced ATR activity.
• Disrupting the PHF8-TOPBP1 axis suppresses breast tumorigenesis and confers vulnerability to PARP inhibitors (PARPi) and platinum drugs.
• Breast tumor cells with PHF8 loss-of-function mutations show increased sensitivity to PARPi.

Conclusions:

• The PHF8-TOPBP1 signaling pathway is implicated in breast tumorigenesis.
• Targeting this pathway offers potential therapeutic avenues for PHF8-TOPBP1 proficient tumors.
• Loss-of-function mutations in PHF8 serve as a predictive biomarker for PARPi efficacy in breast cancer.