Mitochondrial targeted catalase suppresses invasive breast cancer in mice

BMC Cancer

Research Article

Warren Ladiges¹  Christina Pettan-Brewer¹  Linda Enns¹  Soroosh Fatemie¹  Heather Hopkins¹  John Morton¹  Jorming Goh² 

[1] Department of Comparative Medicine, University of Washington, 98195, Seattle, WA, USA;Department of Comparative Medicine, University of Washington, 98195, Seattle, WA, USA;Interdisciplinary Program in Nutritional Sciences, University of Washington, 98195, Seattle, WA, USA;

关键词: Reactive Oxygen Species;    Mammary Tumor;    Invasive Breast Cancer;    Reactive Oxygen Species Level;    Intracellular Reactive Oxygen Species;   

DOI  :  10.1186/1471-2407-11-191

 received in 2010-11-24, accepted in 2011-05-23,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundTreatment of invasive breast cancer has an alarmingly high rate of failure because effective targets have not been identified. One potential target is mitochondrial generated reactive oxygen species (ROS) because ROS production has been associated with changes in substrate metabolism and lower concentration of anti-oxidant enzymes in tumor and stromal cells and increased metastatic potential.MethodsTransgenic mice expressing a human catalase gene (mCAT) were crossed with MMTV-PyMT transgenic mice that develop metastatic breast cancer. All mice (33 mCAT positive and 23 mCAT negative) were terminated at 110 days of age, when tumors were well advanced. Tumors were histologically assessed for invasiveness, proliferation and metastatic foci in the lungs. ROS levels and activation status of p38 MAPK were determined.ResultsPyMT mice expressing mCAT had a 12.5 per cent incidence of high histological grade primary tumor invasiveness compared to a 62.5 per cent incidence in PyMT mice without mCAT. The histological grade correlated with incidence of metastasis with 56 per cent of PyMT mice positive for mCAT showing evidence of pulmonary metastasis compared to 85.4 per cent of PyMT mice negative for mCAT with pulmonary metastasis (p ≤ 0.05). PyMT tumor cells expressing mCAT had lower ROS levels and were more resistant to hydrogen peroxide-induced oxidative stress than wild type tumor cells, suggesting that mCAT has the potential of quenching intracellular ROS and subsequent invasive behavior. The metastatic tumor burden in PyMT mice expressing mCAT was 0.1 mm2/cm2 of lung tissue compared with 1.3 mm2/cm2 of lung tissue in PyMT mice expressing the wild type allele (p ≤ 0.01), indicating that mCAT could play a role in mitigating metastatic tumor progression at a distant organ site. Expression of mCAT in the lungs increased resistance to hydrogen peroxide-induced oxidative stress that was associated with decreased activation of p38MAPK suggesting ROS signaling is dependent on p38MAPK for at least some of its downstream effects.ConclusionTargeting catalase within mitochondria of tumor cells and tumor stromal cells suppresses ROS-driven tumor progression and metastasis. Therefore, increasing the antioxidant capacity of the mitochondrial compartment could be a rational therapeutic approach for invasive breast cancer.Please see related commentary article: http://www.biomedcentral.com/1741-7015/9/62

【 授权许可】

Unknown   
© Goh et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.