Glypican-3 (GPC3) is a membrane-bound heparan sulfate proteoglycan that is mutated in the SimpsonGolabi-Behmel syndrome. This is an X-linked condition characterized by overgrowth, and various visceral and skeletal dysmorphisms. The phenotype of the SimpsonGolabi-Behmel syndrome patients and GPC3-de®cient mice, as well as gene transfection experiments indicate that GPC3 can act as an inhibitor of cell proliferation and survival. It has been previously shown that GPC3 expression is downregulated in mesotheliomas and ovarian cancer. Here we report that GPC3 expression is also silenced in human breast cancer, and that this silencing is due, at least in part, to hypermethylation of the GPC3 promoter. Ectopic expression of GPC3 inhibited growth in eight out of 10 breast cancer cell lines. Collectively, these data suggest that GPC3 can act as a negative regulator of breast cancer growth. Oncogene (2001) 20, 7408 ± 7412.Keywords: glypicans; breast cancer; DNA methylation Glypicans are a family of heparan sulfate proteoglycans that are attached to the cell surface by a glycosylphosphatidylinositol anchor (Bern®eld et al., 1999;Filmus et al., 2000;Filmus, 2001). Glypican-3 (GPC3), a member of the glypican family, is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS) . This is an X-linked condition characterized by pre-and postnatal overgrowth, and a broad spectrum of clinical manifestations that vary from a mild phenotype in carrier females to infantile lethal forms in some males (Behmel et al., 1984;Garganta et al., 1992;Golabi et al., 1984;Neri et al., 1998). The list of abnormalities observed in SGBS patients can include a distinct facial appearance, and malformations involving craniofacial development (macroglossia, cleft lip/palate, dental malocclusion), chest/skeleton (polydactyly, syndactyly, supernumerary nipples, supernumerary ribs), genitalia (hypospadias, cryptorchidism), and internal organs (cardiac defects, diaphragmatic hernias, renal cystic dysplasia) (Garganta et al., 1992;Hughes-Benzie et al., 1996;Neri et al., 1998). An increased risk for the development of pediatric tumors has also been reported (HughesBenzie et al., 1992).The phenotype of SGBS patients and of GPC3-de®cient mice (Cano-Gauci et al., 1999) suggests that during development GPC3 can act as an inhibitor of cell proliferation, and as an inducer of apoptosis in speci®c tissues. Experimental evidence has been provided supporting such a role for GPC3 in various cell lines (Duenas Gonzales et al., 1998). Currently, the mechanism by which GPC3 regulates cell proliferation and survival is not clear. It has been proposed that GPC3 can act as a negative regulator of insulin-like growth factor II , but this remains to be proven. There is also genetic evidence that, at least in certain tissues, GPC3 can regulate bone morphogenetic factors (Grisaru et al., 2001; PaineSaunders et al., 2000), but it seems unlikely that this regulation is the direct cause of the overgrowth observed in GPC3 patients.It has been recently reported that GPC3 ex...

Our results suggest that overexpression of CD44s could be relevant in determining the highly invasive behaviour of gliomas, though it does not behave as an independent prognostic factor for survival.

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