Cell populations in human breast cancers are molecularly and biologically distinct with age

Adrienne Parsons^{1

2

3

4}, Esther Sauras Colón^{1

5}, Meghana Manjunath^{1

2}, Hanyun Zhang^{6

7}, Julia Chen^{6

7}, Milos Spasic^{1

2}, Beyza Koca^{2

3

4}, Busem Binboga Kurt^{2

8

9}, Rachel A Freedman^{2

3

4

10}, Elizabeth A Mittendorf^{3

4

9

10}, Alexander Swarbrick^{6

7}, Peter van Galen^{11

12

13

14

15}, Sandra S McAllister^{16

17

18

19

20}

Affiliations

¹ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA.
⁵ Oncological Pathology and Bioinformatics Research Group, Hospital Verge de la Cinta, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tortosa, Spain.
⁶ Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁷ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
⁸ Department of Pathology, Mass General Brigham, Boston, MA, USA.
⁹ Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Breast Cancer Program, Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
¹¹ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. pvangalen@bhw.harvard.edu.
¹² Department of Medicine, Harvard Medical School, Boston, MA, USA. pvangalen@bhw.harvard.edu.
¹³ Broad Institute of Harvard and MIT, Cambridge, MA, USA. pvangalen@bhw.harvard.edu.
¹⁴ Harvard Stem Cell Institute, Cambridge, MA, USA. pvangalen@bhw.harvard.edu.
¹⁵ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. pvangalen@bhw.harvard.edu.
¹⁶ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. smcallister1@bwh.harvard.edu.
¹⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA. smcallister1@bwh.harvard.edu.
¹⁸ Breast Cancer Program, Dana-Farber/Harvard Cancer Center, Boston, MA, USA. smcallister1@bwh.harvard.edu.
¹⁹ Broad Institute of Harvard and MIT, Cambridge, MA, USA. smcallister1@bwh.harvard.edu.
²⁰ Harvard Stem Cell Institute, Cambridge, MA, USA. smcallister1@bwh.harvard.edu.

PMID: 41188599
DOI: 10.1038/s43587-025-00984-1

Cell populations in human breast cancers are molecularly and biologically distinct with age

Adrienne Parsons et al. Nat Aging. 2025.

. 2025 Nov 4.

doi: 10.1038/s43587-025-00984-1. Online ahead of print.

Authors

Affiliations

¹ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA.
⁵ Oncological Pathology and Bioinformatics Research Group, Hospital Verge de la Cinta, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tortosa, Spain.
⁶ Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁷ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
⁸ Department of Pathology, Mass General Brigham, Boston, MA, USA.
⁹ Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Breast Cancer Program, Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
¹¹ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. pvangalen@bhw.harvard.edu.
¹² Department of Medicine, Harvard Medical School, Boston, MA, USA. pvangalen@bhw.harvard.edu.
¹³ Broad Institute of Harvard and MIT, Cambridge, MA, USA. pvangalen@bhw.harvard.edu.
¹⁴ Harvard Stem Cell Institute, Cambridge, MA, USA. pvangalen@bhw.harvard.edu.
¹⁵ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. pvangalen@bhw.harvard.edu.
¹⁶ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. smcallister1@bwh.harvard.edu.
¹⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA. smcallister1@bwh.harvard.edu.
¹⁸ Breast Cancer Program, Dana-Farber/Harvard Cancer Center, Boston, MA, USA. smcallister1@bwh.harvard.edu.
¹⁹ Broad Institute of Harvard and MIT, Cambridge, MA, USA. smcallister1@bwh.harvard.edu.
²⁰ Harvard Stem Cell Institute, Cambridge, MA, USA. smcallister1@bwh.harvard.edu.

PMID: 41188599
DOI: 10.1038/s43587-025-00984-1

Abstract

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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Update of

Cell Populations in Human Breast Cancers are Molecularly and Biologically Distinct with Age.
Parsons A, Colon ES, Spasic M, Kurt BB, Swarbrick A, Freedman RA, Mittendorf EA, van Galen P, McAllister SS. Parsons A, et al. Res Sq [Preprint]. 2024 Oct 15:rs.3.rs-5167339. doi: 10.21203/rs.3.rs-5167339/v1. Res Sq. 2024. Update in: Nat Aging. 2025 Nov 4. doi: 10.1038/s43587-025-00984-1. PMID: 39483921 Free PMC article. Updated. Preprint.

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Cell populations in human breast cancers are molecularly and biologically distinct with age

Affiliations

Cell populations in human breast cancers are molecularly and biologically distinct with age

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

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LinkOut - more resources

Full Text Sources

Miscellaneous