Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer.
Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer.
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DOI：
10.1158/0008-5472.can-16-2350
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Li M;Chen Q;Yu X
人们对限制 BRCA1 突变导致的家族性乳腺癌和卵巢癌风险升高的实际策略仍然抱有极大的兴趣。在这里，我们报告，在 BRCA1 缺陷型乳腺癌小鼠模型中，限制活性氧 (ROS) 的产生足以减少 DNA 损伤并延缓肿瘤发生。我们记录了模型乳腺中大量的内源性雌激素氧化代谢物，这些代谢物诱导了与DNA双链断裂和基因组不稳定相关的DNA加合物和无嘌呤/无嘧啶位点。通过抗氧化剂治疗抑制雌激素氧化可减少氧化性 DNA 损伤并延缓乳腺肿瘤的发生。总体而言，我们的工作为为什么种系 BRCA1 突变会导致组织特异性肿瘤这一长期存在的问题提供了答案，并展示了组织特异性、ROS 诱导的 DNA 损伤如何产生非遗传力来促进 BRCA1 缺陷小鼠的乳腺肿瘤。我们的研究结果为评估合适的抗氧化方式作为家族性乳腺癌的化学预防策略奠定了基础。
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 non-genetic 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.