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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Detection of an increased number of T cells overexpressing p16INK4a in patients with breast cancer treated with different chemotherapeutic agents indicates that immunosenescence can occur as a bystander effect of treatment.
“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]
The Discussion (page unavailable) reports increased p16INK4a expression in T cells after breast-cancer chemotherapy and concludes that chemotherapy promotes senescence markers in CD3+ lymphocytes. But the Methods (page unavailable) describe measuring expression in isolated T-cell samples, not counting T cells that overexpress p16INK4a; the paper also does not establish a bystander mechanism. (LLM, conf=0.86)
Experimental — accuracy not yet measuredT cell p16 levels increase following chemotherapy.
“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]
Cytotoxic chemotherapy increases cellular senescence (higher p16INK4a expression) in the haematopoietic compartment in patients with breast cancer and induces long-lasting elevation of SASP factors VEGFA and CCL2.
“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]
Senescence markers have been detected in human breast cancer samples from patients treated with chemotherapy.
“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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Self-citation
- 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
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › 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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