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Open Access Research article

Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene

Lisa Becks12, Misty Prince12, Hannah Burson12, Christopher Christophe12, Mason Broadway12, Ken Itoh3, Masayuki Yamamoto4, Michael Mathis25, Elysse Orchard16, Runhua Shi27, Jerry McLarty27, Kevin Pruitt28, Songlin Zhang29 and Heather E Kleiner-Hancock12*

Author Affiliations

1 Department of Pharmacology, Toxicology and Neuroscience, LSUHSC-S, Shreveport, Louisiana, USA

2 Breast Cancer Focus Group, Feist-Weiller Cancer Center, Shreveport, Louisiana, USA

3 Center for Advanced Medical Research, Hirosaki University School of Medicine, Hirosaki, Japan

4 Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

5 Department of Anatomy & Cellular Biology, LSUHSC-S, Shreveport, Louisiana, USA

6 Department of Veterinary Medicine, LSUHSC-S, Shreveport, Louisiana, USA

7 Department of Medicine, LSUHSC-S, Shreveport, Louisiana, USA

8 Department of Molecular & Cellular Physiology, LSUHSC-S, Shreveport, Louisiana, USA

9 Department of Pathology, LSUHSC-S, Shreveport, Louisiana, USA

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BMC Cancer 2010, 10:540  doi:10.1186/1471-2407-10-540

Published: 8 October 2010

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.