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Effect of Cytotoxic Chemotherapy on Markers of Molecular Age in Patients With Breast Cancer
Open accessAbstract
BACKGROUND: Senescent cells, which express p16 (INK4a) , accumulate with aging and contribute to age-related pathology. To understand whether cytotoxic agents promote molecular aging, we measured expression of p16 (INK4a) and other senescence markers in breast cancer patients treated with adjuvant chemotherapy. METHODS: Blood and clinical information were prospectively obtained from 33 women with stage I to III breast cancer at four time points: before anthracycline-based chemotherapy, immediately after anthracycline-based chemotherapy, 3 months after anthracycline-based chemotherapy, and 12 months after anthracycline-based chemotherapy. Expression of senescence markers p16 (INK4a) and ARF mRNA was determined using TaqMan quantitative reverse-transcription polymerase chain reaction in CD3(+) T lymphocytes, telomere length was determined by Southern analysis, and senescence-associated cytokines were determined by enzyme-linked immunosorbent assay. Findings were independently assessed in a cross-sectional cohort of 176 breast cancer survivors enrolled a median of 3.4 years after treatment; 39% previously received chemotherapy. All statistical tests were two-sided. RESULTS: In prospectively analyzed patients, expression of p16 (INK4a) and ARF increased immediately after chemotherapy and remained elevated 12 months after treatment. Median increase in log2 p16 (INK4a) was 0.81 (interquartile range = 0.28-1.62; Wilcoxon signed-rank P < .001), or a 75% absolute increase in expression, equivalent to the increase observed over 14.7 years of chronological aging. ARF expression was comparably increased (P < .001). Increased expression of p16 (INK4a) and ARF was associated with dose-dense therapy and hematological toxicity. Expression of two senescence-associated cytokines (VEGFA and MCP1) was durably increased by adjuvant chemotherapy. Telomere length was not affected by chemotherapy. In a cross-sectional cohort, prior chemotherapy exposure was independently associated with a log2-increase in p16 (INK4a) expression of 0.57 (repeated measures model, P < .001), comparable with 10.4 years of chronological aging. CONCLUSIONS: Adjuvant chemotherapy for breast cancer is gerontogenic, inducing cellular senescence in vivo, thereby accelerating molecular aging of hematopoietic tissues.
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“the detection of an increased number of Tcells overexpressing p16 INK4a in patients with breast cancer treated with different chemotherapeutic agents is a finding worth highlighting because it indicates that immunosenescence can occur as a bystander effect of treatment 99,100 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [99]
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“to increase following chemotherapy;30”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [30]
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“Another study showed that cytotoxic chemotherapy increases cellular senescence (higher p16 INK4a expression) in the haematopoietic compartment in patients with breast cancer and induces long- lasting elevation of the SASP factors VEGFA and CCL2 (ref. 99 ) .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [99]
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“senescence markers have been detected in human breast cancer samples from patients treated with chemotherapy [343].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [343]
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Metadata
- Authors
- Sanoff, H. K., Deal, A. M., Krishnamurthy, J., Torrice, C., Dillon, P., Sorrentino, J., Ibrahim, J. G., Jolly, T. A., Williams, G., Carey, L. A., Drobish, A., Gordon, B.-B., Alston, S., Hurria, A., Kleinhans, K., Rudolph, K. L., Sharpless, N. E., & Muss, H. B.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-03-28
- Volume
- 106
- Issue
- 4
- Pages
- dju057-dju057
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC3982894
- OpenAlex
- W2126729859
- Cited by
- 283
- References
- 54
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 26 · 2023: 24 · 2022: 35 · 2021: 34 · 2020: 31 · 2019: 15 · 2018: 20 · 2017: 17 · 2016: 19 · 2015: 18 · 2014: 8
- FWCI
- 13.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Breast Cancer Research Foundation
- Glenn Foundation for Medical Research
- National Institutes of Health (2k12ca120780-16, 5r01ag024379-15, AG024379)
- National Institute on Aging (AG024379)
- National Cancer Institute (K12-CA120780, K07CA106722, P50CA058223, P30CA016086)
- National Institute of Environmental Health Sciences (P30ES010126, T32ES007126)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Keywords
- breast cancer, cytotoxic chemotherapy, molecular aging, cellular senescence, p16INK4a, ARF, anthracycline chemotherapy, adjuvant chemotherapy, dose-dense chemotherapy, hematologic toxicity, VEGF-A, MCP-1, telomere length, T cells, hematopoietic tissue
- MeSH terms
- Adult, Aged, Animals, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Cross-Sectional Studies, Female, Humans, Middle Aged, Neoplasm Staging, Prospective Studies, T-Lymphocytes, Biomarkers, Cytokines, Telomere, Cellular Senescence, Anthracyclines, Cyclin-Dependent Kinase Inhibitor p16, Reverse Transcriptase Polymerase Chain Reaction, ADP-Ribosylation Factors, Mice
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