Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion

Melissa L T Teoh; Matthew P Fitzgerald; Larry W Oberley; Frederick E Domann

doi:10.1158/0008-5472.CAN-09-1195

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Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion

Journal article

Open access

Peer reviewed

Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion

Melissa L T Teoh, Matthew P Fitzgerald, Larry W Oberley and Frederick E Domann

Cancer research (Chicago, Ill.), Vol.69(15), pp.6355-6363

08/01/2009

DOI: 10.1158/0008-5472.CAN-09-1195

PMCID: PMC2728021

PMID: 19602586

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https://doi.org/10.1158/0008-5472.CAN-09-1195View

Published (Version of record) Open Access

Abstract

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, EcSODDeltaHBD 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.

RNA, Small Interfering - genetics

Up-Regulation

Heparin, Low-Molecular-Weight - pharmacology

Superoxide Dismutase - genetics

Superoxide Dismutase - biosynthesis

Humans

Gene Expression Regulation, Neoplastic

Vascular Endothelial Growth Factor A - metabolism

Breast Neoplasms - therapy

RNA, Messenger - biosynthesis

Breast Neoplasms - enzymology

Transfection

Superoxides - metabolism

Transcription, Genetic

Superoxide Dismutase - metabolism

Neoplasm Invasiveness

Down-Regulation

RNA, Messenger - genetics

Gene Expression Regulation, Enzymologic

Breast Neoplasms - genetics

Glucuronidase - biosynthesis

Glucuronidase - genetics

Breast Neoplasms - pathology

Heparan Sulfate Proteoglycans - metabolism

Cell Line, Tumor

Details

Title: Subtitle: Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion
Creators: Melissa L T Teoh - Department of Radiation Oncology, Roy J and Lucille A Carver College of Medicine, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
Matthew P Fitzgerald
Larry W Oberley
Frederick E Domann
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.69(15), pp.6355-6363
Publisher: United States
DOI: 10.1158/0008-5472.CAN-09-1195
PMID: 19602586
PMCID: PMC2728021
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: R01 CA073612-10 / NCI NIH HHS R29 CA073612 / NCI NIH HHS CA115438 / NCI NIH HHS CA073612 / NCI NIH HHS R01 CA115438-03 / NCI NIH HHS R01 CA073612-09 / NCI NIH HHS R01 CA115438-02 / NCI NIH HHS R01 CA115438 / NCI NIH HHS R56 CA073612 / NCI NIH HHS P30CA086862 / NCI NIH HHS R01 CA073612 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 08/01/2009
Academic Unit: Pathology; Surgery; Radiation Oncology
Record Identifier: 9984047704402771

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