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Originally published online as doi:10.2353/ajpath.2008.080275 on August 18, 2008 Originally published online as doi:10.2353/ajpath.2008.080275 on August 7, 2008

Published online before print August 7, 2008
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(American Journal of Pathology. 2008;173:844-855.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080275

An Antimetastatic Role for Decorin in Breast Cancer

Silvia Goldoni*{ddagger}, Daniela G. Seidler*{ddagger}, Jack Heath*{ddagger}, Matteo Fassan{dagger}, Raffaele Baffa{dagger}, Mathew L. Thakur§, Rick T. Owens, David J. McQuillan and Renato V. Iozzo*{ddagger}

From the Department of Pathology, Anatomy and Cell Biology,* and Urology,{dagger} Thomas Jefferson University, Philadelphia, Pennsylvania, the Cancer Cell Biology and Signaling Program,{ddagger} Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, Department of Radiology,§ the Radiopharmaceutical Research Center, Thomas Jefferson University, Philadelphia, Pennsylvania and the LifeCell Corporation, Branchburg, New Jersey

Decorin, a member of the small leucine-rich proteoglycan gene family, down-regulates members of the ErbB receptor tyrosine kinase family and attenuates their signaling, leading to growth inhibition. We investigated the effects of decorin on the growth of ErbB2-overexpressing mammary carcinoma cells in comparison with AG879, an established ErbB2 kinase inhibitor. Cell proliferation and anchorage-independent growth assays showed that decorin was a potent inhibitor of breast cancer cell growth and a pro-apoptotic agent. When decorin and AG879 were used in combination, the inhibitory effect was synergistic in proliferation assays but only additive in both colony formation and apoptosis assays. Active recombinant human decorin protein core, AG879, or a combination of both was administered systemically to mice bearing orthotopic mammary carcinoma xenografts. Primary tumor growth and metabolism were reduced by approximately 50% by both decorin and AG879. However, no synergism was observed in vivo. Decorin specifically targeted the tumor cells and caused a significant reduction of ErbB2 levels in the tumor xenografts. Most importantly, systemic delivery of decorin prevented metastatic spreading to the lungs, as detected by novel species-specific DNA detection and quantitative assays. In contrast, AG879 failed to have any effect. Our data support a role for decorin as a powerful and effective therapeutic agent against breast cancer due to its inhibition of both primary tumor growth and metastatic spreading.






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