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Affiliations of authors: Women's Malignancies Branch (SW, LE, TR, DP, BG, NMF, PSS), DNA Replication Group, Laboratory of Molecular Pharmacology (MIA, HF), and Tumor Biology Section, Radiation Biology Branch (JBM), Center for Cancer Research, National Cancer Institute, Bethesda, MD; Department of Oncology, Military Institute of Medicine, Warsaw, Poland (RD); Laboratory Animal Sciences Program, Frederick National Laboratory, Frederick MD (YQ); Departments of Pathology and Laboratory Medicine (SB), and Departments of Medicine (GS, YG-P), Indiana University School of Medicine, Indianapolis, IN; Department of Pathology (WB), and Department of Oncology and Radiotherapy (ES-Z, JJ), Medical University of Gdańsk, Gdańsk, Poland; Department of Neurosurgery, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland (TM); Department of Neurosurgery and Children's Neurosurgery Clinic, Medical University of Lublin, Lublin, Poland (TT); Department of Neurosurgery, Interior Affairs Hospital, Olsztyn, Poland (WO); Department of Clinical Oncology, Białystok Oncology Center, Białystok, Poland (BC-A); Present addresses: Teach for America, Baltimore, MD (LE); National Heart, Lung, and Blood Institute, Bethesda, MD (DP); Cancer Biology Program (NMF), and Department of Oncology (GS), Stanford University, Stanford, CA.
Published: July 2014
AI Article Synopsis
Article 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.
