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Free Radic Biol Med. 2018 May 20;120:133-146. doi: 10.1016/j.freeradbiomed.2018.03.012. Epub 2018 Mar 14.

The biological age linked to oxidative stress modifies breast cancer aggressiveness.

Author information

1
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain. Electronic address: maria_del_mar@usal.es.
2
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain. Electronic address: adrianblanco@usal.es.
3
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Departamento de Bioquímica y Biología Molecular I, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain. Electronic address: scastillolluva@usal.es.
4
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain. Electronic address: auroragvrm@gmail.com.
5
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Instituto Nacional de Cancerología, Bogotá, D.C., Colombia. Electronic address: jmgalvis@usal.es.
6
Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Servicio de Bioquímica Clínica, Hospital Universitario de Salamanca, Salamanca, Spain. Electronic address: mcmartin@saludcastillayleon.es.
7
Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Servicio de Bioquímica Clínica, Hospital Universitario de Salamanca, Salamanca, Spain. Electronic address: misidoro@usal.es.
8
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain. Electronic address: lhontecillas-ibis@us.es.
9
Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain. Electronic address: mbgc@usal.es.
10
Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain. Electronic address: fjgc@usal.es.
11
Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Departamento de Estadística, Universidad de Salamanca, Spain. Electronic address: carpatino@usal.es.
12
Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: pgalindo@usal.es.
13
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: jhmao@lbl.gov.
14
Bioinformatics Service, Nucleus, University of Salamanca (USAL), Salamanca, Spain. Electronic address: cprietos@usal.es.
15
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain. Electronic address: andres.castellanos@irbbarcelona.org.
16
Institute for Bioinformatics, University Medicine Greifswald, Greifswald, Germany. Electronic address: lars.kaderali@uni-greifswald.de.
17
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, Spain. Electronic address: jperezlosada@usal.es.

Abstract

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.

KEYWORDS:

Aging; Biological age; Breast cancer; Mouse genetics; Oxidative stress; Subphenotypes

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