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- Title
Patterns of cell cycle checkpoint deregulation associated with intrinsic molecular subtypes of human breast cancer cells.
- Authors
Bower, Jacquelyn J.; Vance, Leah D.; Psioda, Matthew; Smith-Roe, Stephanie L.; Simpson, Dennis A.; Ibrahim, Joseph G.; Hoadley, Katherine A.; Perou, Charles M.; Kaufmann, William K.
- Abstract
Genomic instability is a hallmark of breast cancer, contributes to tumor heterogeneity, and influences chemotherapy resistance. Although Gap 2 and mitotic checkpoints are thought to prevent genomic instability, the role of these checkpoints in breast cancer is poorly understood. Here, we assess the Gap 2 and mitotic checkpoint functions of 24 breast cancer and immortalized mammary epithelial cell lines representing four of the six intrinsic molecular subtypes of breast cancer. We found that patterns of cell cycle checkpoint deregulation were associated with the intrinsic molecular subtype of breast cancer cell lines. Specifically, the luminal B and basal-like cell lines harbored two molecularly distinct Gap 2/mitosis checkpoint defects (impairment of the decatenation Gap 2 checkpoint and the spindle assembly checkpoint, respectively). All subtypes of breast cancer cell lines examined displayed aberrant DNA synthesis/Gap 2/mitosis progression and the basal-like and claudin-low cell lines exhibited increased percentages of chromatid cohesion defects. Furthermore, a decatenation Gap 2 checkpoint gene expression signature identified in the cell line panel correlated with clinical outcomes in breast cancer patients, suggesting that breast tumors may also harbor defects in decatenation Gap 2 checkpoint function. Taken together, these data imply that pharmacological targeting of signaling pathways driving these phenotypes may lead to the development of novel personalized treatment strategies for the latter two subtypes which currently lack targeted therapeutic options because of their triple negative breast cancer status. Cell cycle: Breast cancer subtypes exhibit distinct checkpoint dysfunctions Unique subtypes of breast cancer display distinctive patterns of genomic instability that affect cell division. Jacquelyn J. Bower and colleagues at the University of North Carolina at Chapel Hill, USA, assessed the molecular function of several G2-M cell cycle checkpoints—which ensure that cells don't begin mitotic cell division until DNA replication is complete and they have had a chance to repair any damaged DNA—in 24 breast cancer and mammary epithelial cell lines that collectively represent four of the six intrinsic molecular subtypes of breast cancer. The distinct patterns of cell cycle checkpoint deregulation that the researchers found suggest that pharmacological targeting of the dysfunction in each type of breast cancer could lead to personalized treatment strategies. The findings also point to diagnostic biomarkers that could help predict patient responses to novel drugs or existing chemotherapies.
- Publication
NPJ Breast Cancer, 2017, Vol 3, Issue 1, pN.PAG
- ISSN
2374-4677
- Publication type
Article
- DOI
10.1038/s41523-017-0009-7