1. DNA double-strand break repair genes and oxidative damage in brain metastasis of breast cancer.
- Author
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Woditschka S, Evans L, Duchnowska R, Reed LT, Palmieri D, Qian Y, Badve S, Sledge G Jr, Gril B, Aladjem MI, Fu H, Flores NM, Gökmen-Polar Y, Biernat W, Szutowicz-Zielińska E, Mandat T, Trojanowski T, Och W, Czartoryska-Arlukowicz B, Jassem J, Mitchell JB, and Steeg PS
- Subjects
- Animals, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms prevention & control, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Neuroprotective Agents pharmacology, Spin Labels, Up-Regulation, Antioxidants pharmacology, Brain Neoplasms secondary, Breast Neoplasms pathology, Cyclic N-Oxides pharmacology, DNA Breaks, Double-Stranded, DNA Repair genetics, Oxidative Stress, Rad51 Recombinase metabolism, Reactive Oxygen Species metabolism, Tumor Suppressor Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
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., (Published by Oxford University Press 2014.)
- Published
- 2014
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