Computational decoding of cell-cycle phase effects on cancer hallmarks across breast cancer subtypes

Breast tumors have traditionally been categorized into four subtypes. Recent single-cell advancements, however, reveal that tumors can contain multiple subtypes, reflecting intrinsic heterogeneity. Relatedly, whilst the crucial role of cell cycle regulation in cancer development is widely acknowledged, the impact of cell cycle phases on oncogenic signaling within these subtypes remains unresolved. Here, we examine differences in transcriptomic hallmarks across and within cell cycle phases and breast cancer subtypes in two large single-cell cohorts. We show that accounting for cell cycle phases reveals a broader pool of hallmark pathways while preserving those identified when phases are ignored. Moreover, we pinpoint FDA approved drugs that can target hallmarks within specific phase-subtype combinations. This study highlights the critical role of cell cycle phases in advancing our understanding of cancer biology. The distinct mechanisms observed here suggest that targeting these hallmarks may offer a more precise and effective strategy for patient treatment.