Combined Dusp4 and p53 loss with Dbf4 amplification drives tumorigenesis via cell cycle restriction and replication stress escape in breast cancer
Authors
Ann Hanna, Mellissa J. Nixon, M. Valeria Estrada, Violeta Sanchez, Quanhu Sheng, Susan R. Opalenik, Abigail L. Toren, Joshua Bauer, Phillip Owens, Frank M. Mason, Rebecca S. Cook, Melinda E. Sanders, Carlos L. Arteaga, Justin M. Balko
Institution
Vanderbilt University, Nashville
Country
United States
Year
2022
Journal
Breast Cancer Research
Abstract
Deregulated signaling pathways are a hallmark feature of oncogenesis and driver of tumor progression. Dual specificity protein phosphatase 4 (DUSP4) is a critical negative regulator of the mitogen-activated protein kinase (MAPK) pathway and is often deleted or epigenetically silenced in tumors. DUSP4 alterations lead to hyperactivation of MAPK signaling in many cancers, including breast cancer, which often harbor mutations in cell cycle checkpoint genes, particularly in TP53. We found that Dusp4 loss alone is insufficient in mediating tumorigenesis, but alternatively converges with loss in Trp53 and MYC amplification to induce tumorigenesis primarily through chromosome 5 amplification, which specifically upregulates Dbf4, a cell cycle gene that promotes cellular replication by mediating cell cycle checkpoint escape. This study identifies a novel mechanism for breast tumorigenesis implicating Dusp4 loss and p53 mutations in cellular acquisition of Dbf4 upregulation as a driver of cellular replication and cell cycle checkpoint escape.
Product use
Isolation and culture of murine primary mammary epithelial cells