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J Natl Cancer Inst. 2014 Apr;106(4):dju057. doi: 10.1093/jnci/dju057. Epub 2014 Mar 28.

Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer.

Author information

  • 1Affiliations of authors: Lineberger Comprehensive Cancer Center (HKS, AMD, JK, CT, JS, JGI, LAC, AD, B-BG, SA, NES, HBM), Department of Medicine (HKS, TAJ, GW, LAC, NES, HBM), Department of Genetics (JK, CT, NES), and Department of Biostatistics (JGI), University of North Carolina, Chapel Hill, NC; Department of Medicine, University of Virginia, Charlottesville, VA (PD); Department of Medical Oncology and Therapeutics Research, City of Hope Cancer Center, Duarte, CA (AH); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (KK, KLR).

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.

Comment in

PMID:
24681605
[PubMed - indexed for MEDLINE]
PMCID:
PMC3982894
[Available on 2015/4/1]
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