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 using patient data and experimental investigations. We find thatATMmutation 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 inATRalone are rare,ATR/TP53co-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 inTP53mutant, not wild-type, cells. Overall, we identify mode of cell cycle dysregulation as a distinct event that determines subtype, metastatic potential, and treatment responsiveness, providing rationale for reconsidering diagnostic classification through the lens of the mode of cell cycle dysregulation..