A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas

Bui, Thuan D.; Rankin, Julia; Smith, Kelly J.; Huguet, Emmanuel; Ruben, Steve; Strachan, Tom; Harris, Adrian L.; Lindsay, Susan

doi:10.1038/sj.onc.1200936

Cited by 83 publications

(57 citation statements)

References 15 publications

(22 reference statements)

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“…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 glycoproteins identified as putative inhibitors of the Wnt signalling pathway (Jones and Jomary, 2002).…”

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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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Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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“…Recent studies have indicated that unlike CDK4, overexpression of CDK2 may not provide a bene®t to neoplastic cells; constitutive CDK2 expression did not rescue cells from either p53 or TGFb induced growth arrest (Ewen et al, 1993b;Latham et al, 1996). Two other potential proto-oncogenes, WNT1 and WNT10b, were similarly not ampli®ed in any of the tumors (van't Veer et al, 1984;Bui et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…The SAS (sarcoma ampli®ed sequence; Meltzer et al, 1991;Jankowski et al, 1994) gene is located in this region, as well as a number of other genes including MDM2 (a p53 associated protein; Oliner et al, 1992;Leach et al, 1993) and CDK4 cyclin dependent kinase (Matsushime et al, 1994;Khatib et al, 1993). Recently, CDK2 cyclin dependent kinase, WNT1 and WNT10b have also been mapped to this chromosomal region, although their amplification status in tumors has not been thoroughly examined (Arheden et al, 1988;Demetrick et al, 1994;Bui et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas

et al. 1999

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Ampli®cation of genes in the 12q13-15 region occurs frequently in several malignancies including osteosarcoma. The products of these ampli®ed genes are thought to provide cancer cells with a selective growth advantage; however, the speci®c gene(s) driving this amplicon is unknown. We have previously shown that the SAS gene is ampli®ed in most parosteal osteosarcomas. In this study we analysed additional putative growth regulatory genes in this chromosomal region in 24 primary osteosarcoma specimens. CDK4 and SAS were coampli®ed in 6/6 parosteal tumors, and MDM2 was also ampli®ed in 4/5 parosteal cases. In comparison, ampli®cation occurred in only 2/16 classical intramedullary osteosarcomas and involved the SAS gene. Each ampli®ed gene had a correspondingly elevated mRNA level. Four high grade intramedullary tumors had elevated mRNA expression of SAS, but did not exhibit gene ampli®cation. Gene ampli®cation/overexpression was not associated with metastatic disease and did not change markedly with tumor progression, as evidenced by analysis of sequential tumor specimens from eight patients. Three other genes in the 12q13-15 region (CDK2, WNT1 and WNT10b) were not ampli®ed in any of the tumors. The di erent patterns of gene ampli®ca-tion and overexpression of CDK4, SAS and MDM2 in parosteal and intramedullary osteosarcomas may help explain the disparity in the biological behaviour of these two types of osteosarcoma.

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“…In humans, there are nine Wnt genes known [Wntl (van Ooyen et al, 1985), Wnt2 (Wainright et al, 1988), Wnt3 (Roelink et al, 1993), Wnt5a (Clark et al, 1993;Lejeune et al, 1995), Wnt3a, Wnt4, Wnt7a and Wnt7b (Huguet et al, 1994), and WntlOb (Bui et al, 1997a)]. Four Wnt genes (Wnt2, 4, Sa and 7b) are more highly expressed in human breast carcinomas compared with normal breast tissues (Huguet et al, 1994;Lejeune et al, 1995).…”

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Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma

Bui

Zhang²,

Rees³

et al. 1997

Br J Cancer

124

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Summary Wnt genes are transforming to mouse breast epithelium and are hormonally regulated in vivo. To assess their role in another endocrine-responsive human cancer, the expression of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a, 7b and 1 Ob) in normal human endometrium and endometrial cells, and endometrial carcinoma tissues and cell lines was investigated by ribonuclease protection analysis. Wnt2, 3, 4 and 5a mRNAs but not Wnt7a, 7b or 10b mRNAs were expressed in primary culture of normal endometrial epithelial (NEE) and stromal (NES) cells. In contrast, in four endometrial carcinoma cell lines (RL95-2, HEC-1 -A, AN3 CA and Ishikawa), Wnt2 and Wnt3 mRNAs were absent. Wnt4 was expressed in only one out of four cell lines (RL95-2), and Wnt5a was much lower. Wnt7a and Wnt7b mRNAs were expressed in three out of four cell lines (RL95-2, HEC-1 -A and Ishikawa). WntlOb mRNA was expressed in RL95-2 and AN3 CA. In fresh tissues, all Wnt genes apart from WntlOb were expressed in normal endometrium and endometrial carcinoma. Similar to the cell lines, the level of Wnt4 mRNA expression was significantly higher in the normal endometrium than endometrial carcinoma. Wnt2, 3 and 5a mRNAs were also lower in endometrial carcinoma compared with normal endometrium. There was no difference in the level of Wnt2, 3, 4 and 5a mRNA expression between proliferative phase and secretory phase of the menstrual cycle, or between either menstrual phase and the first trimester of pregnancy. In vitro, progesterone and/or 1 7,l-oestradiol had no effect on Wnt2, 3, 4, 5a and 7b mRNA expression in NES and all endometrial carcinoma cell lines. The data indicate that all Wnt genes were expressed in vitro, six out of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a and 7b) were expressed endogenously in the human endometrium, their mRNA expression was hormonally independent and Wnt4 gene downregulation as well as down-regulation of Wnt 2, 3 and 5a may be associated with endometrial carcinoma.

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A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas

Cited by 83 publications

References 15 publications

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas

Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma

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