Circadian rhythms as orchestrators of breast cancer metastasis: From molecular mechanisms to chronotherapeutic interventions

Circadian rhythms orchestrate physiological processes through molecular clocks, regulating up to 43% of genes and influencing breast cancer progression. This review synthesizes recent evidence linking circadian disruption-from shift work, light-at-night exposure, and social jetlag-to increased breast cancer risk and metastasis. Epidemiological studies, including large cohorts like the Nurses' Health Study III, show a 78% higher risk with long-term night shifts, mediated by hormonal disruptions and accelerated cellular aging. Molecular mechanisms reveal subtype-specific clock gene alterations: luminal tumors exhibit estrogen-driven dysrhythmia, HER2-positive tumors show signaling pathway disruptions, and triple-negative tumors feature epigenetic silencing. EMT, invasion, and niche preparation display temporal regulation, with chronodisruption promoting protumorigenic environments. Clinical evidence supports chronotherapy, timing treatments like chemotherapy and immunotherapy to circadian phases for enhanced efficacy and reduced toxicity. Biomarkers from wearables enable personalized interventions, addressing health disparities in shift workers. Integrating circadian biology into oncology promises transformative precision medicine, with ongoing trials validating chronotherapeutic protocols.