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Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) is the most common molecular subtype in breast cancer (BC), but drug resistance remains an unsolved problem, particularly in metastatic ones. Cell-cycle related genes play a crucial role in tumorigenesis and progression. However, their relationship with drug resistance and patient prognosis is not yet clear. Here, we introduce a novel and robust HR+/HER2- BC Prognostic Signature (HBPS) based on cell cycle-related gene expression and Cox analysis. 421 h+/HER2- BC patients from the TCGA dataset were used as the training set and 3605 patients from GEO and cBioPortal datasets were used as the validation sets. Subsequently, we explored the underlying biological mechanisms and drug susceptibility associated with the HBPS score. Patients with high HBPS scores exhibited significantly worse prognosis across all sets. The high HBPS score group demonstrated lower levels of immune cell infiltration, downregulation of HALLMARK_KRAS_SIGNALING_DN and HALLMARK_IL2-STAT5 signaling. Moreover, further validation revealed that CDKN2C (one critical gene in the HBPS) deficiency was associated with immuno-cold tumor microenvironment and enhanced HR + HER2- breast cancer cells aggressiveness. Overall, the study's biological insights, crucial for comprehending and tackling drug resistance, hold the potential to inform precise drug treatments in HR+/HER2- BC patients.