Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer

Proc Natl Acad Sci U S A. 2024 Feb 13;121(7):e2311854121. doi: 10.1073/pnas.2311854121. Epub 2024 Feb 6.

Abstract

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular circadian rhythms in noncancerous and cancerous human breast tissues and their clinical relevance are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For noncancerous breast tissue, inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of luminal A samples exhibit continued, albeit dampened and reprogrammed rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude luminal A tumors. Surprisingly, patients with high-magnitude tumors had reduced 5-y survival. Correspondingly, 3D luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

Keywords: breast cancer; circadian data ordering; circadian medicine; metastasis; prognosis.

MeSH terms

  • Breast Neoplasms* / pathology
  • Circadian Clocks* / genetics
  • Circadian Rhythm
  • Estrogens
  • Female
  • Humans
  • Prognosis

Substances

  • Estrogens