Methylation-associated silencing of SFRP1 with an 8p11–12 amplification inhibits canonical and non-canonical WNT pathways in breast cancers


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Abstract

Recently, we analysed the 8p11–12 genomic region for copy number and gene expression changes in a panel of human breast cancer cell lines and primary specimens. We found thatSFRP1(Secreted frizzled related protein 1) is frequently under expressed even in breast tumours with copy number increases in this genomic region.SFRP1 encodes a WNT signalling antagonist, and plays a role in the development of multiple solid tumour types. In this study, we analysed methylation-associated silencing of theSFRP1gene in breast cancer cells with the 8p11–12 amplicon, and investigated the tumour suppressor properties of SFRP1 in breast cancer cells. SFRP1 expression was markedly reduced in both the breast cancer cell lines and primary tumour specimens relative to normal primary human mammary epithelial cells even whenSFRP1is amplified. Suppression of SFRP1 expression in breast cancer cells with anSFRP1gene amplification is associated withSFRP1promoter methylation. Furthermore, restoration of SFRP1 expression suppressed the growth of breast cancer cells in monolayer, and inhibited anchorage independent growth. We also examined the relationship between the silencing ofSFRP1gene and WNT signalling in breast cancer. Ectopic SFRP1 expression in breast cancer cells suppressed both canonical and non-canonical WNT signalling pathways, and SFRP1 expression was negatively associated with the expression of a subset of WNT responsive genes includingRETandMSX2.Thus, down-regulation of SFRP1 can be triggered by epigenetic and/or genetic events and may contribute to the tumourigenesis of human breast cancer through both canonical and non-canonical WNT signalling pathways. © 2009 UICC

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