Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness

Cell cycle dysregulation is prerequisite for cancer formation. However, it is unknown whether the mode of dysregulation affects disease characteristics. Here, we conduct comprehensive analyses of cell cycle checkpoint dysregulation events in breast cancer using patient data complemented by experimental investigations in multiple model systems: genetically-engineered mice, patient-derived xenografts, biomatrices, and cell lines. We find that ATM mutation predisposes the diagnosis of primary estrogen receptor (ER)+/human epidermal growth factor (HER)2- cancer in older women. Conversely, CHK2 dysregulation induces formation of metastatic, premenopausal ER+/HER2- breast cancer (p=0.001) that is treatment-resistant (HR=6.15, p=0.01). Lastly, while mutations in ATR alone are rare, ATR/TP53 co-mutation is 12-fold enriched over expected in ER+/HER2- disease (p=0.002) and associates with metastatic progression (HR=2.01, p=0.006). Concordantly, ATR dysregulation induces metastatic phenotypes in TP53 mutant, but not wild-type, cells. These results newly identify a role for distinct cell cycle dysregulation events in determining cancer subtype, metastatic potential, and treatment responsiveness. Statement of Significance These findings reframe the paradigm of cancer classification by demonstrating that cell cycle dysregulation decisions during malignant transformation can causally direct the type of cancer that evolves, its metastatic potential, and treatment responsiveness. These results provide rationale for delineating mode of checkpoint kinase dysregulation to improve diagnostic and therapeutic choices.