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Overexpression of Extracellular Superoxide Dismutase Attenuates Heparanase Expression and Inhibits Breast Carcinoma Cell Growth and Invasion

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine, and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa

Requests for reprints: Frederick Domann, Free Radical and Radiation Biology Program, B180 Medical Laboratories, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242. Phone: 319-335-8018; Fax: 319-335-8039; E-mail: frederick-domann{at}uiowa.edu.

Key Words: invasion • heparanase • extracellular superoxide dismutase • heparan sulfate • reactive oxygen species

Increased expression of heparanase stimulates the progression of various human cancers, including breast cancer. Therefore, a deeper understanding of the mechanisms involved in regulating heparanase is critical in developing effective treatments for heparanase-overexpressing cancers. In this study, we investigated the potential use of extracellular superoxide dismutase (EcSOD) to enhance the inhibitory effects of heparin/low molecular weight heparin (LMWH) in breast cancer cells. EcSOD binds to cell surfaces and the extracellular matrix through heparin-binding domain (HBD). Deleting this HBD rendered the protein a more potent inhibitor of breast cancer growth, survival, and invasion. Among the treatment combinations examined, EcSODHBD plus LMWH provided the best tumor suppressive effects in inhibiting breast cancer growth and invasion in vitro. We have further shown that overexpression of EcSOD decreased accumulation of vascular endothelial growth factor in the culture medium and increased the level of intact cell surface-associated heparan sulfate, thus implicating inhibition of heparanase expression as a potential mechanism. Overexpression of EcSOD inhibited steady-state heparanase mRNA levels by >50% as determined by quantitative reverse transcription-PCR. Moreover, heparanase promoter activation was suppressed by EcSOD as indicated by a luciferase reporter assay. These findings reveal a previously unrecognized molecular pathway showing that regulation of heparanase transcription can be mediated by oxidative stress. Our study implies that overexpression of EcSOD is a promising strategy to enhance the efficacy of heparin/LMWH by inhibiting heparanase as a novel treatment for breast cancer. [Cancer Res 2009;69(15):6355–63]