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J. Biol. Chem., Vol. 282, Issue 20, 14906-14915, May 18, 2007

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Shedding of Syndecan-1 by Stromal Fibroblasts Stimulates Human Breast Cancer Cell Proliferation via FGF2 Activation^*

Gui Su, Stacy A. Blaine, Dianhua Qiao, and Andreas Friedl¹

From the Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison and Pathology and Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Madison, Wisconsin 53705

The cell surface heparan sulfate proteoglycan syndecan-1 is induced in stromal fibroblasts of breast carcinomas and participates in a reciprocal feedback loop, which stimulates carcinoma cell growth in vitro and in vivo. To define the molecular mechanism of carcinoma growth stimulation, a three-dimensional co-culture model was developed that combines T47D breast carcinoma cells with immortalized human mammary fibroblasts in collagen gels. By silencing endogenous syndecan-1 induction with short interfering RNA and expressing mutant murine syndecan-1 constructs, it was determined that carcinoma cell mitogenesis required proteolytic shedding of syndecan-1 from the fibroblast surface. The paracrine growth signal was mediated by the syndecan-1 heparan lfate chains rather than the ectodomain of the core protein and required fibroblast growth factor 2 and stroma-derived factor 1. This paracrine pathway may provide an opportunity for the therapeutic disruption of stromaepithelial signaling.

Received for publication, December 21, 2006

^* This work was supported by Susan G. Komen Foundation Grant BCTR0402969 and National Institutes of Health Grant R01CA107012-01A1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, Clinical Sciences Center K4/812, University of Wisconsin-Madison, 600 Highland Ave., Madison, WI 53792-8550. Tel.: 608-265-9283; Fax: 608-265-6215; E-mail: afriedl{at}wisc.edu.

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