Subtype-specific circadian clock dysregulation modulates breast cancer biology, invasiveness, and prognosis.

Hammarlund, J. A.; Li, S.-Y.; Wu, G.; Lian, J.-W.; Howell, S. J.; Clarke, R.; Adamson, A.; Goncalves, C. F.; Hogenesch, J. B.; Meng, Q.-J. A.; Anafi, R. C.

doi:10.1101/2023.05.17.540386

bioRxiv · 10.1101/2023.05.17.540386

Subtype-specific circadian clock dysregulation modulates breast cancer biology, invasiveness, and prognosis.

Hammarlund, J. A.·Li, S.-Y.·Wu, G.·Lian, J.-W.·Howell, S. J.·Clarke, R.·Adamson, A.·Goncalves, C. F.·Hogenesch, J. B.·Meng, Q.-J. A.·Anafi, R. C.

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Abstract

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms in non-cancerous and cancerous human breast tissues are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For non-cancerous tissue, the inferred order of core-circadian genes matches established physiology. 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 disrupted 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. Patients with high-magnitude tumors had reduced 5-year 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.

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Hammarlund, J. A., Li, S.-Y., Wu, G., Lian, J.-W., Howell, S. J., Clarke, R., Adamson, A., Goncalves, C. F., Hogenesch, J. B., Meng, Q.-J. A., Anafi, R. C.. 2023-05-19. Subtype-specific circadian clock dysregulation modulates breast cancer biology, invasiveness, and prognosis.. https://doi.org/10.1101/2023.05.17.540386

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