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

Syndecan-1 is a cell-surface, heparan-sulphate proteoglycan (HSPG) predomin antly expressed by epithelial cells. It binds specifically to many proteins , including oncoproteins. For example, it induces the assembly of a signall ing complex between FCF ligands and their cognate receptors(1). But so far there has been no direct evidence that this proteoglycan contributes to tum origenesis. Here we have examined the role of syndecan-1 (encoded by Sdc1) during mammary tumour formation in response to the ectopic expression of th e 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 d evelopment of solitary tumours (median time 22 weeks(3)). We show that in S dc1(-/-) mice, Wnt-1-induced hyperplasia in virgin mammary gland was reduce d by 70%, indicating that the Wnt-1 signalling pathway was inhibited. Of th e 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 ectodom ain purified from mouse mammary epithelial cells stimulates the activity of a Wnt-1 homologue in a tissue culture assay. Our results provide both gene tic and biochemical evidence that syndecan-1 can modulate Wnt signalling, a nd is critical for Wnt-1-induced tumorigenesis of the mouse mammary gland.