A frequent activated smoothened mutation in sporadic basal cell carcinomas

The hedgehog signalling pathway in tumorigenesis and development

“…While overexpression of wild type smoothened did not result in a tumour phenotype, ectopic expression of an activated smoothened gene under the control of the Keratin-5 promoter resulted in a microscopic skin phenotype consistent with BCCs, although no developmental anomalies were noted (Xie et al, 1998). The smoothened gene in this case carried the Trp535Leu missense mutation observed in up to 20% of BCCs (Lam et al, 1999;Xie et al, 1998). The absence of developmental anomalies in these mice ®ts with restricted expression in the skin of a membrane bound protein, while these anomalies in the K14-Shh mice may result from di usion of ectopically expressed Sonic hedgehog.…”

“…Given that constitutive activation of smoothened is likely to upregulate transcription of hedgehog target genes in the same way as patched inactivation, it is not surprising that activating mutations in the smoothened gene have been detected in 10 ± 20% of sporadic BCCs (Lam et al, 1999;Reifenberger et al, 1998;Xie et al, 1998). In particular one common mutation (Trp535Leu) in the seventh transmembrane domain of smoothened has been detected in several independent studies in up to 20% of BCCs (Lam et al, 1999;Xie et al, 1998).…”

“…In particular one common mutation (Trp535Leu) in the seventh transmembrane domain of smoothened has been detected in several independent studies in up to 20% of BCCs (Lam et al, 1999;Xie et al, 1998). In contrast to wild-type smoothened, the mutant form has been shown to result in constitutive smoothened signalling in an in vitro focus forming assay and in transgenic mice (Xie et al, 1998).…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…BCC, the most common human cancer consistently has abnormalities of the hedgehog pathway with PTCH1 mutations in 50% human sporadic BCCs, suggesting alteration of additional genes in the hedgehog pathway in this type of skin cancer. Indeed, mutations of SMO are found in about 10% of sporadic BCCs (Reifenberger et al, 1998(Reifenberger et al, , 2005Xie et al, 1998;Lam et al, 1999;Couve-Privat et al, 2002). Unlike wildtype SMO, expression of activated SMO molecules in mouse skin results in formation of BCC-like tumors (Xie et al, 1998).…”

Targeting the CB2 cannabinoid receptor in osteoporosis

“…Likewise, inactivating mutations in Ptch or SuFu underlie the Gorlin syndrome that predisposes to the development of BCC and/or medulloblastoma [76,77]. Conversely, mutations in the Smo gene that confer gain-of-function to the encoded protein are also found in human BCCs and, rarely, in medulloblastomas [78], but exogenous targeted expression of a mutant human Smo gene from BCC in transgenic mice similarly induces cutaneous carcinomas, medulloblastomas and rhabdomyosarcomas. Collectively, the reiteration of tumor development in mice by the same genetic aberrations that are found in human tumors of the same class validates the oncogenic nature of unrestricted hedgehog/Gli signaling in this limited subset of tissues.…”