Journal article
Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v 121(7), e2311854121
13 Feb 2024
PMID: 38319971
Featured in Collection : UN Sustainable Development Goals @ Drexel
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. Significance Collecting time- course breast cancer biopsies is difficult. As a result, the influence of daily rhythms on breast tumor biology remains a mystery and physicians cannot personalize the timing of cancer therapies. We used machine learning to overcome this barrier, integrating data from hundreds of patients and ordering these data along circadian time. We identified rhythmic genes and pathways in normal human breast tissue and dampened and reprogrammed rhythms in luminal A breast cancers. Critically, patients with luminal A tumors that showed stronger global expression rhythms had an reduced 5- y survival. These same tumors showed increased cycling of EMT pathway genes. Using 3D cultures of patient- derived tumor cells, we show that luminal A clocks regulate cell invasion and metastasis.
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Details
- Title
- Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer
- Publication Details
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v 121(7), e2311854121
- Publisher
- NATL ACAD SCIENCES; WASHINGTON
- Grant note
- J.A.H., G.W., J.B.H., and R.C.A. were supported by the National Cancer Institute (5R01CA227485) . S.-Y.L., S.J.H., R.B.C., and Q.-J.M. were supported by the Breast Cancer Now grant (2022FebPR1518) . S.-Y.L. and Q.-J.M. were also supported by the Helen Muir Fund from the Wellcome Centre for Cell-Matrix Research (088785/Z/09) . R.C.A. received additional support from 5R01AG068577. J.-W.L. was supported by a Medical Research Council PhD Studentship. We thank the MCRC Biobank for access to clinical breast samples and pathological characterizations. We thank Prof. Charles Streuli for the design of this project. We thank Dr. Dharshika Pathiranage and Ms. Xiangjun Zhao for their assistance with various experiments. We are grateful to the many patients who contributed the samples used in this analysis.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001169158600002
- Scopus ID
- 2-s2.0-85184549814
- Other Identifier
- 991021861291804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology