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

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In a study reported in the Journal of the National Cancer Institute, Woditschka and colleagues identified a role for the DNA repair genes BARD1 and RAD51 and oxidative damage in brain metastases in breast cancer. The two genes were implicated in expression profiling of 23 matched resected brain metastases and primary breast tumors; metastases overexpressed both BARD1 and RAD1 compared with the matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001) and compared with unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008).

Overexpression of either gene in a mouse model using MDA-MB-231-BR cells increased brain metastases by three- to fourfold after intracardiac injections but not lung metastases after tail-vein injection. Short-hairpin RNA knockdown of RAD51 in a model using 4T1-BR cells reduced brain metastases by 2.5-fold without affecting development of lung

Studies in vitro showed that cells overexpressing BARD1 and RAD51 had reduced genomic instability but did not exhibit growth and colonization phenotypes until DNA damage was induced. Reactive oxygen species were found in tumor cells and at high levels in the metastatic neuroinflammatory microenvironment, and use of a brain-permeating oxygen radical scavenger inhibited brain metastasis induced by BARD1 and RAD51overexpression.

The investigators concluded, “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.” ■

Woditschka S, et al: J Natl Cancer Inst 106(7):dju145, 2014.




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