Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene
Lisa Becks1, Misty Prince, Hannah Burson
1Department of Pharmacology, LSUHSC-S, Shreveport, Louisiana, USA.
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.
Insights
Mice lacking the Nrf2 gene showed faster, more aggressive mammary tumors. This suggests Nrf2 plays a crucial role in controlling mammary cancer progression, not just initial lesion formation.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Nuclear factor erythroid 2-related factor (Nrf2) regulates oxidative stress genes via the antioxidant response element (ARE).
- Nrf2 activation is a target for cancer chemoprevention by phytochemicals.
- Auraptene, a citrus coumarin, was investigated for its potential Nrf2-activating effects on mammary lesions.
Purpose of the Study:
- To investigate the role of Nrf2 in mammary carcinogenesis.
- To determine if auraptene suppresses premalignant mammary lesions via Nrf2/ARE activation.
- To assess the susceptibility of Nrf2 knockout (KO) mice to mammary carcinogenesis.
Main Methods:
- Mammary premalignant lesions and carcinomas were induced using medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene.
- Wild-type (WT) and Nrf2 KO mice were fed control or auraptene-containing diets.
- Statistical analyses included ANOVA, Kaplan-Meier survival, and Mann-Whitney U-test.
Main Results:
- No differences in premalignant lesions were observed between genotypes or diets.
- Nrf2 KO mice exhibited significantly increased mammary carcinoma growth rate, size, and weight.
- KO mice showed lower mammary tumor-free survival and increased active NF-κB and β-catenin in tumors.
- Incidences of lung adenomas were higher in KO mice compared to WT mice.
Conclusions:
- Nrf2 deficiency leads to rapid and aggressive mammary carcinoma progression, independent of initial lesion formation.
- Nrf2 plays a critical role in suppressing mammary tumor growth and aggressiveness.
- Further research into Nrf2's role in cancer progression is warranted.
