Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer.
There remains great interest in practical strategies to limit the elevated risks of familial breast and ovarian cancers driven by BRCA1 mutation. Here, we report that limiting the production of reactive oxygen species (ROS) is sufficient to reduce DNA lesions and delay tumorigenesis in a murine model of BRCA1-deficient breast cancer. We documented a large amount of endogenous estrogen oxidative metabolites in the mammary gland of the model, which induced DNA adducts and apurinic/apyrimidinic sites associated with DNA double-strand breaks and genomic instability. Repressing estrogen oxidation via antioxidant treatments reduced oxidative DNA lesions and delayed the onset of mammary tumors. Overall our work suggests an answer to the long-standing question of why germline BRCA1 mutations cause tissue-specific tumors, in showing how tissue-specific, ROS-induced DNA lesions create a nongenetic force to promote mammary tumors in BRCA1-deficient mice. Our findings create a rationale for evaluating suitable antioxidant modalities as a chemopreventive strategy for familial breast cancer. Cancer Res; 77(2); 448-58. ©2016 AACR.
Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.|Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, California.
Mo
M
Li
Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, California.
Qian
Q
Chen
Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, California. xyu@coh.org.
Xiaochun
X
Yu
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics
D016588:Anticarcinogenic Agents; D000975:Antioxidants; C575444:BAP1 protein, mouse; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase