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

Shi-Yang Li, Jan A Hammarlund, Gang Wu, Jia-Wen Lian, Sacha J Howell, Robert B Clarke, Antony D Adamson, Cátia F Gonçalves, John B Hogenesch, Ron C Anafi, Qing-Jun Meng

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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.

Original languageEnglish
Pages (from-to)e2311854121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number7
DOIs
Publication statusPublished - 6 Feb 2024

Keywords

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

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