Combined Dusp4 and p53 loss with Dbf4 amplification drives tumorigenesis via cell cycle restriction and replication stress escape in breast cancer

Ann Hanna
Vanderbilt University
May 23, 2022
Breast Cancer Res
https://pubmed.ncbi.nlm.nih.gov/35850776

This article is currently being updated. View its version on PubMed.

https://pubmed.ncbi.nlm.nih.gov/35850776

Research summary

This study investigates the cooperative role of Dusp4 loss, p53 deletion, and Dbf4 amplification in promoting breast cancer tumorigenesis. Using a genetically engineered mouse model with mammary-specific deletion of Dusp4, researchers demonstrated that Dusp4 loss alone is insufficient to drive tumorigenesis. However, when combined with Trp53 loss and MYC amplification, there is a significant increase in tumor formation, characterized by replication stress escape and cell cycle deregulation. The study highlights the amplification of Dbf4 as a key event facilitating these oncogenic processes.

Key outcome of the study

The combination of Dusp4 and p53 loss, along with Dbf4 amplification, synergistically drives breast cancer tumorigenesis by enabling cells to overcome replication stress and bypass cell cycle checkpoints.

Mouse model

Conditional Dusp4 floxed mouse model developed by genOway, enabling mammary-specific deletion of Dusp4 to study its role in breast cancer development.

TARGET:
Dusp4, Trp53, Dbf4
Dual specificity phosphatase 4 (DUSP4), Tumor protein p53 (TP53), DBF4 zinc finger (Dbf4)

Keywords

Breast cancer, Tumorigenesis, Cell cycle regulation, Replication stress, DUSP4, p53, Dbf4

Technical specifications

Conditional Knockout model, Cre-loxP system, Mammary-specific gene deletion, Gene amplification studies

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