Abstract
Background
Epidemiological studies have linked psychological stress with an increased risk of breast cancer, however few studies have linked stress hormone signalling to cancer initiation mechanistically. This may be particularly pertinent in populations already at risk due to mutations in the cancer predisposition genes BRCA1/2.
Methods
Here we employ BRCA1/2 knockdown in breast and prostate epithelial cells to examine the effects of the stress hormone cortisol on DNA damage and repair. We perform a retrospective analysis of plasma cortisol and urinary 8-OHdG in a female BRCA-mutation carriers cohort (nā=ā62) and validate our findings in a male cohort (nā=ā70).
Results
Cortisol promotes DNA damage in normal mammary epithelial cells, and in a BRCA-deficient setting, delays DNA repair. In female BRCA-mutation carriers higher plasma cortisol levels are associated with an increased risk of cancer. In a male BRCA-mutation cohort risk of prostate cancer was also significantly increased in those with higher cortisol levels. Urinary 8-OHdG, a biomarker of oxidative DNA damage, was also correlated with a risk of breast cancer and prostate cancer.
Conclusion
Taken together these findings demonstrate that psychological stress, through the induction of DNA damage by cortisol, may increase the cumulative risk of cancer in BRCA-mutation carriers.
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Data availability
The datasets generated during and/or analysed during the current study are not publicly available due to participant confidentiality but are available from the corresponding author on reasonable request.
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Acknowledgements
We are indebted to all of the men and women who are taking part in this study. We also would like to thank the research collaborators and steering committee (Appendix A).
Funding
MF is supported by Rosetrees Trust. The clinical studies are coordinated by the Institute of Cancer Research, London, UK and supported by grants from Cancer Research UK (Grant references (C5047/A21332, C5047/A13232 and C5047/A17528), The Ronald and Rita McAulay Foundation, Prostate Cancer UK ā London Movember Centre of Excellence (CEO13_2-002), and the support of the NIHR to the Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.
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Contributions
Conceptualisation and funding ā MSF and RE. Sample collection ā EB, EP and RE. Experimental design and investigations ā RLF, MF, BAP. Data processing and analysis -RLF, MF and ARH. Writing, review and editing ā RLF, MSF, MF, EB, EP, RE and ASH.
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Competing interests
Professor Rosalind Eeles has the following conflicts of interest to declare: Honoraria from GU-ASCO, Janssen, University of Chicago, Dana Farber Cancer Institute USA as a speaker. Educational honorarium from Bayer and Ipsen, member of external expert committee to Astra Zeneca UK and Member of Active Surveillance Movember Committee. She is a member of the SAB of Our Future Health. She undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK. The remaining authors declare no competing interest.
Ethical approval
The IMPACT study protocol was reviewed and approved by the West-Midlands Research and Ethics Committee in the UK (reference: 05/MRE07/25) and subsequently by each participating institutionās local committee. All participants provided written consent, and the study was performed in accordance with the Declaration of Helsinki. The clinical studies are coordinated by the Institute of Cancer Research, London, UK. This project represents independent research supported by The National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
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Flaherty, R.L., Falcinelli, M., Hesketh, A.R. et al. Biomarkers of psychological stress are associated with increased susceptibility to the development of breast and prostate cancer in BRCA1/2 mutation carriers. Br J Cancer 133, 615ā624 (2025). https://doi.org/10.1038/s41416-025-03085-3
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DOI: https://doi.org/10.1038/s41416-025-03085-3
