Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene.
Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene.
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DOI：
10.1186/1471-2407-10-540
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发表时间：
2010-10-08
期刊：
影响因子：
3.8
通讯作者：
Kleiner-Hancock HE
中科院分区：
文献类型：
--
作者：
Becks L;Prince M;Burson H;Christophe C;Broadway M;Itoh K;Yamamoto M;Mathis M;Orchard E;Shi R;McLarty J;Pruitt K;Zhang S;Kleiner-Hancock HE
核因子红细胞2相关因子（Nrf2）属于碱性亮氨酸拉链转录因子家族，其激活是癌症化学预防植物化学物质的策略。它是氧化应激诱导的基因的重要调节剂，如谷胱甘肽S-转移酶，血红素加氧酶-1和peroxiredoxin 1，通过激活抗氧化反应元件（ARE）。我们假设（1）柑橘香豆素金萝卜素可能通过激活Nrf2/ARE抑制癌前乳腺病变，（2）Nrf2敲除（KO）小鼠更容易发生乳腺癌。用醋酸甲羟孕酮和7，12-二甲基苯并[a]蒽诱发癌前病变和乳腺癌。进行了10周的癌前研究，其中8组雌性野生型（WT）和KO小鼠，每组10只，饲喂对照饮食或含有橙皮油烯（500 ppm）的饮食。还在KO与WT小鼠中进行了致癌性研究（n = 30 - 34）。使用ANOVA和Kaplan-Meier生存统计量以及Mann-Whitney U检验评价组间比较。所有用致癌物处理的小鼠都表现出癌前病变，但基因型或饮食没有差异。在KO小鼠中，乳腺癌生长速率、大小和重量显著增加。尽管总生存期没有差异，但KO小鼠的无乳腺肿瘤生存期显著较低。此外，在KO乳腺癌中，NF-κ B和β-连环蛋白的活性形式增加了约2倍，而氧化蛋白没有观察到差异。观察到许多其他肿瘤，包括淋巴瘤。有趣的是，KO小鼠中肺腺瘤的发生率显著高于WT小鼠。我们首次报道，在癌前病变的形成方面没有明显差异，但KO小鼠表现出快速的侵袭性乳腺癌进展。
Activation of nuclear factor erythroid 2-related factor (Nrf2), which belongs to the basic leucine zipper transcription factor family, is a strategy for cancer chemopreventive phytochemicals. It is an important regulator of genes induced by oxidative stress, such as glutathione S-transferases, heme oxygenase-1 and peroxiredoxin 1, by activating the antioxidant response element (ARE). We hypothesized that (1) the citrus coumarin auraptene may suppress premalignant mammary lesions via activation of Nrf2/ARE, and (2) that Nrf2 knockout (KO) mice would be more susceptible to mammary carcinogenesis. Premalignant lesions and mammary carcinomas were induced by medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene treatment. The 10-week pre-malignant study was performed in which 8 groups of 10 each female wild-type (WT) and KO mice were fed either control diet or diets containing auraptene (500 ppm). A carcinogenesis study was also conducted in KO vs. WT mice (n = 30-34). Comparisons between groups were evaluated using ANOVA and Kaplan-Meier Survival statistics, and the Mann-Whitney U-test. All mice treated with carcinogen exhibited premalignant lesions but there were no differences by genotype or diet. In the KO mice, there was a dramatic increase in mammary carcinoma growth rate, size, and weight. Although there was no difference in overall survival, the KO mice had significantly lower mammary tumor-free survival. Also, in the KO mammary carcinomas, the active forms of NF-κB and β-catenin were increased ~2-fold whereas no differences in oxidized proteins were observed. Many other tumors were observed, including lymphomas. Interestingly, the incidences of lung adenomas in the KO mice were significantly higher than in the WT mice. We report, for the first time, that there was no apparent difference in the formation of premalignant lesions, but rather, the KO mice exhibited rapid, aggressive mammary carcinoma progression.
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影响因子：
254.7
作者：
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通讯作者：
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DOI：
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