Cited by 283Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsReproductive Biology and Fertility

Effect of Cytotoxic Chemotherapy on Markers of Molecular Age in Patients With Breast Cancer

Open access
Sanoff, Hanna K., Deal, Allison M., Krishnamurthy, Janakiraman, Torrice, Chad, Dillon, Patrick, Sorrentino, Jessica, Ibrahim, Joseph G., Jolly, Trevor A. +10 more·2014·JNCI: Journal of the National Cancer Institute

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/jnci/dju057

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 measured
  • T cell p16 levels increase following chemotherapy.

    “to increase following chemotherapy;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]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

2 of the 54 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

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)
Venue
JNCI: Journal of the National Cancer Institute
Published
2014-03-28
Volume
106
Issue
4
Pages
dju057-dju057
ISSN
  • 0027-8874 (ISSN-L)
  • 1460-2105
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review