Cell populations in human breast cancers are molecularly and biologically distinct with age
Aging is associated with increased breast cancer risk, and the oldest and youngest patients have worse outcomes, irrespective of subtype. It is unknown how age affects cells in the breast tumor microenvironment or how they contribute to age-related pathology. Here we discover age-associated differences in cell states in human estrogen receptor-positive and triple-negative breast cancers using analyses of existing bulk and single-cell transcriptomic data. We generate and apply an Age-Specific Program ENrichment (ASPEN) analysis pipeline, revealing age-related changes, including increased tumor cell epithelial-mesenchymal transition and cancer-associated fibroblast inflammatory responses in triple-negative breast cancer. Estrogen receptor-positive breast cancer displays increased ESR1 expression and reduced vascular and immune cell metabolism with age. Cell interactome analysis reveals candidate signaling pathways that drive age-related cell states. Spatial analyses across independent clinical cohorts support the computational findings. This work identifies potential targets for age-adapted therapeutic interventions for breast cancer.
Authors
- Peter van Galen (ORCID: https://orcid.org/0000-0002-0735-1570)
- Elizabeth A. Mittendorf (ORCID: https://orcid.org/0000-0002-9762-8536)
- Milos Spasic (ORCID: https://orcid.org/0000-0001-5451-7003)
- Hanyun Zhang (ORCID: https://orcid.org/0000-0002-4140-7881)
- Alexander Swarbrick (ORCID: https://orcid.org/0000-0002-3051-5676)
- Julia Chen (ORCID: https://orcid.org/0000-0003-1278-7763)
- Esther Sauras-Colón (ORCID: https://orcid.org/0000-0003-1649-938X)
- Busem Binboğa Kurt (ORCID: https://orcid.org/0000-0002-7161-1496)
- Sandra S. McAllister (ORCID: https://orcid.org/0000-0002-5111-5903)
- Rachel A. Freedman (ORCID: https://orcid.org/0000-0003-0460-674X)
- Adrienne Parsons
- Meghana Manjunath
- Beyza Koca (ORCID: https://orcid.org/0000-0002-8695-4424)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Garvan Institute of Medical Research (AU)
- UNSW Sydney (AU)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Harvard Stem Cell Institute (US)
- Dana-Farber Brigham Cancer Center (US)
- Mass General Brigham (US)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1038/s43587-025-00984-1
- Citations
- 2
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- U.S. Department of Defense
- American Association for Cancer Research
- Breast Cancer Research Foundation
- Global Fund for Women
- MPN Research Foundation
- Edward P. Evans Foundation
- Vera and Joseph Dresner Foundation
- Pelotonia
- National Breast Cancer Foundation
- Petre Foundation
- National Institutes of Health
- Ludwig Center at Harvard
- Medical Research Council
- National Health and Medical Research Council
- National Cancer Institute
- Congressionally Directed Medical Research Programs