Mitochondrial targeted catalase suppresses invasive breast cancer in mice

Abstract

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

Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect

“…Similarly, Ladiges and colleagues used transgenic expression of catalase (targeted to mitochondria) to reduce metastatic tumor burden nearly 13-fold in MMTV-PyMT mice (a mouse model of breast cancer). [50][51][52] What are the possible implications of anti-oxidant therapies for breast cancer patients? Ambrosone and colleagues have shown that a particular allele of the catalase gene in humans (the CC genotype) is associated with higher catalase activity, and a near 20% reduction in breast cancer risk.…”

Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis

“…[47][48][49][50][51][52][53] Transgenic overexpression of catalase in MMTV-PyMT mice (a wellestablished model of breast cancer) reduces tumor aggressiveness (from high-grade to low-grade) and reduces lung metastatic tumor burden by >12-fold. 54,55 Glutathione peroxidase family members also function to detoxify hydrogen peroxide. 56 Of the eight known family members (GPX1-8), it appears that GPX4 is the most relevant to our discussion, as it is targeted to mitochondria.…”

Selective Protection of Normal Cells during Chemotherapy by RY4 Peptides

“…Previous studies have reported the abnormal catalase expression in cancer cells, for example, reduced catalase activity has been confirmed from 24 individual lung tumors compared with tumor-free lung tissues (25). By targeting tumor cell mitochondrial catalase, tumor progression and metastasis are able to be suppressed (26). On the other hand, it has been reported that certain compound is able to increase catalase activity without mRNA upregulation in cells, which indicates the possibility of activity up-and-down space of CAT in cells (27,28).…”