Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors

Klopocki, Eva; Kristiansen, Glen; Wild, Peter J.; Castaños‐Vélez, Esmeralda; Singer, Gad; Stöhr, Robert; Simon, Ronald; Sauter, Guido; Leibiger, H.; Essers, Lutz; Weber, Birgit; Hermann, K.; Rosenthal, André; Hartmann, Arndt; Dahl, Edgar

doi:10.3892/ijo.25.3.641

Cited by 119 publications

(123 citation statements)

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“…Using immunohistochemical analysis, Klopocki et al (2004) found that expression of SFRP1 protein was absent in 46% of invasive breast tumours and in 43% of carcinoma in situ. In addition, two groups recently reported frequent SFRP1 methylation in primary breast tumours (Lo et al, 2006;Veeck et al, 2006), and Bafico et al (2004) clearly demonstrated a novel autocrine mechanism leading to constitutive Wnt signalling in breast cancer, which could be suppressed by SFRP1 and DKK1.…”

Section: Discussionmentioning

confidence: 99%

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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Although mutation of APC or CTNNB1 (b-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a b-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. British Journal of Cancer (2008) Wnt ligands are secreted proteins that bind to transmembrane receptors in the Frizzled (Fz) family. During normal developmental processes, the resultant Wnt signalling plays essential roles in the regulation of cell proliferation, patterning and fate determination (Cadigan and Nusse, 1997). The binding of Wnt to Fz leads to dephosphorylation and stabilisation of b-catenin, enabling it to be translocated into the nucleus, where it interacts with members of the T-cell factor/lymphocyte enhancer factor (TCF/LEF) family of transcription factors to stimulate the expression of target genes. This signalling pathway is strongly implicated in tumorigenesis; indeed, the first mammalian Wnt isoform was identified based on its ability to promote mouse mammary tumorigenesis (Polakis, 2000). In addition, aberrant nuclear and cytoplasmic localisation of b-catenin is frequently observed in human breast cancer (Lin et al, 2000;Ryo et al, 2001;Chung et al, 2004). In contrast to colorectal cancer (CRC), however, mutation of APC, AXIN or CTNNB1 (b-catenin) is rare in breast cancer, indicating that other mechanisms are responsible for the activation of b-catenin. These mechanisms could include increased expression of Wnt ligand (Huguet et al, 1994;Dale et al, 1996;Bui et al, 1997) and/or the loss of Wnt antagonists.Several classes of secreted Wnt antagonists are known, including the Cerberus, Wnt inhibitory factor 1, secreted frizzled-related protein (SFRP) and the Dickkopf (DKK) families (Kawano and Kypta, 2003). The SFRP family is comprised of five secreted glycopr...

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Section: Discussionmentioning

confidence: 99%

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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“…Calponin1 can be used to distinguish invasive from non-invasive breast lesions (Werling et al, 2003). A loss of sfrp1, a Wnt inhibitor, is associated with breast cancer progression and poor prognosis, as is the presence of Ets1 (Klopocki et al, 2004;Lincoln and Bove, 2005). These findings indicate the potential relationship between understanding the mechanisms of normal developmental programmes and gaining understanding of oncogenic growth.…”

Section: Discussionmentioning

confidence: 90%

ERα–CITED1 co-regulated genes expressed during pubertal mammary gland development: implications for breast cancer prognosis

et al. 2007

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Expression microarray analysis identified over 930 genes regulated during puberty in the mouse mammary gland. Most prominent were genes whose expression increased in parallel with pubertal development and remained high thereafter. Members of the Wnt, transforming growth factor-b and oestrogen-signalling pathways were significantly overrepresented. Comparison to expression data from CITED1 knockout mice identified a subset of oestrogen-responsive genes displaying altered expression in the absence of CITED1. Included in this subset are stanniocalcin2 (Stc2) and amphiregulin (Areg). Chromatin immunoprecipitation revealed that ERa binds to oestrogen response elements in both the Stc2 and Areg genes in the mammary gland during puberty. Additionally, CITED1 and ERa localize to the same epithelial cells of the pubertal mammary gland, supporting a role for interaction of these two proteins during normal development. In a human breast cancer data set, expression of Stc2, Areg and CITED1 parallel that of ERa. Similar to ERa, CITED1 expression correlates with good outcome in breast cancer, implying that potential maintenance of the ERa-CITED1 co-regulated signalling pathway in breast tumours can indicate good prognosis.

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“…Therefore, targeting Wnt/β-catenin pathway that is responsible for self-renewal can be a potential therapeutics strategy (Woodward et al, 2007). Although mutation of β-catenin may not commonly occurred in human breast cancers, various studies showed the role of Wnt signaling pathway in pathogenesis of breast cancer (Lin et al, 2000;Jain et al, 2002;Wong et al, 2002;Klopocki et al, 2004) suggesting a link between Wnt signaling and DNA damage response in epithelial cells (Ayyanan et al, 2006).…”

Section: 2789 Application Of Stem Cells In Targeted Therapy Of Breasmentioning

confidence: 99%

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

Madjd

Gheytanchi²,

Erfani³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors

Cited by 119 publications

References 0 publications

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

ERα–CITED1 co-regulated genes expressed during pubertal mammary gland development: implications for breast cancer prognosis

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

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