Journal Article

DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer

Stephan Woditschka, Lynda Evans, Renata Duchnowska, L. Tiffany Reed, Diane Palmieri, Yongzhen Qian, Sunil Badve, George Sledge, Brunilde Gril, Mirit I. Aladjem, Haiqing Fu, Natasha M. Flores, Yesim Gökmen-Polar, Wojciech Biernat, Ewa Szutowicz-Zielińska, Tomasz Mandat, Tomasz Trojanowski, Waldemar Och, Bogumiła Czartoryska-Arlukowicz, Jacek Jassem, James B. Mitchell and Patricia S. Steeg

in JNCI: Journal of the National Cancer Institute

Published on behalf of National Cancer Institute

Volume 106, issue 7 ISSN: 0027-8874
Published online June 2014 | e-ISSN: 1460-2105 | DOI: https://dx.doi.org/10.1093/jnci/dju145
DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer

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Background

Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood.

Methods

Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis–specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group).

Results

Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression.

Conclusions

BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species–mediated genotoxic stress in the metastatic brain.

Journal Article.  7410 words.  Illustrated.

Subjects: Medical Oncology

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