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Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice

Nature Genetics volume 25, pages 329–332 (2000)Cite this article

Abstract

Syndecan-1 is a cell-surface, heparan-sulphate proteoglycan (HSPG) predominantly expressed by epithelial cells. It binds specifically to many proteins, including oncoproteins. For example, it induces the assembly of a signalling complex between FGF ligands and their cognate receptors1. But so far there has been no direct evidence that this proteoglycan contributes to tumorigenesis. Here we have examined the role of syndecan-1 (encoded by Sdc1) during mammary tumour formation in response to the ectopic expression of the proto-oncogene Wnt1. We crossed syndecan-1–deficient mice with transgenic mice that express Wnt1 in mammary gland (TgN(Wnt-1)1Hev; ref. 2). Ectopic Wnt-1 expression induces generalized mammary hyperplasia, followed by the development of solitary tumours (median time 22 weeks3). We show that in Sdc1−/− mice, Wnt-1–induced hyperplasia in virgin mammary gland was reduced by 70%, indicating that the Wnt-1 signalling pathway was inhibited. Of the 39 tumours that developed in a test cohort of mice, only 1 evolved in the Sdc1−/− background. In addition, we show that soluble syndecan-1 ectodomain purified from mouse mammary epithelial cells stimulates the activity of a Wnt-1 homologue in a tissue culture assay. Our results provide both genetic and biochemical evidence that syndecan-1 can modulate Wnt signalling, and is critical for Wnt-1–induced tumorigenesis of the mouse mammary gland.

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Figure 1: Mammary gland morphogenesis is unaffected by a null mutation in Sdc1.
Figure 2: Expression of the Wnt1 transgene is not affected by the Sdc1 genotype.
Figure 3: Mammary tumours are prevented in Sdc1−/− mice.
Figure 4: Syndecan-1 ectodomain can stimulate Wg/Wnt signalling in vitro.

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Acknowledgements

We thank J.A.T. Young, P. Leder and H. Varmus for critical reading of this manuscript. This project was supported by the Charles H. Hood Foundation (C.M.A.) and by the National Institutes of Health (M.B.).

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Authors and Affiliations

  1. Division of Newborn Medicine, Childrens Hospital, Enders 950, Boston, Massachusetts, USA

    Caroline M. Alexander, Michael T. Hinkes, John Lincecum & Merton Bernfield

  2. Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Massachusetts, USA

    Frieda Reichsman, Klaus A. Becker & Susan Cumberledge

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  1. Caroline M. Alexander
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Correspondence to Caroline M. Alexander or Merton Bernfield.

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Alexander, C., Reichsman, F., Hinkes, M. et al. Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice. Nat Genet 25, 329–332 (2000). https://doi.org/10.1038/77108

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