Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer.
Shi-Yang LiJan A HammarlundGang WuJia-Wen LianSacha J HowellRobert B ClarkeAntony D AdamsonCátia F GonçalvesJohn B HogeneschRon C AnafiQing-Jun MengPublished in: Proceedings of the National Academy of Sciences of the United States of America (2024)
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.
Keyphrases
- epithelial mesenchymal transition
- transforming growth factor
- small cell lung cancer
- squamous cell carcinoma
- endothelial cells
- healthcare
- gene expression
- signaling pathway
- mental health
- risk assessment
- oxidative stress
- human health
- rna seq
- heart rate
- transcription factor
- case control
- breast cancer risk
- multidrug resistant
- ultrasound guided
- single cell