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PubMed2003

Sequence variants of the Axin gene in hepatoblastoma.

The Wnt signaling pathway plays critical roles in the embryonic development and tumorigenesis. As a part of the Wnt signal transduction, the function of Axin complex is inhibited, leading to accumulation of beta-catenin. In hepatoblastomas, loss of APC (adenomatous polyposis coli) function or activation of beta-catenin that are the other two components involving in Wnt signaling has been demonstrated. Because hepatoblastoma shows immunohistochemical positivity of beta-catenin more often than its mutation frequency, we analyzed the Axin gene as a candidate to lead beta-catenin accumulation in hepatoblastoma. The coding region of the Axin gene was examined by PCR-SSCP using 24 sets of the primers in 22 hepatoblastomas and some paired normal tissues. Samples revealing aberrant band patterns were subjected to direct sequencing analysis. We identified totally eight variants in the exons and four intronic nucleotide substitutions. Seven variants in the exons were silent mutations, however, the remaining variant at codon 95 (ACG-->ATG) found in one hepatoblastoma predicted to result in an amino acid change from threonine to methionine. The paired peripheral blood DNAs from this patient also showed the same change; we suggested that it was a germline mutation of Axin gene. Our results suggest that mutation of the Axin gene may have a tumorigenic function in a subset of childhood hepatoblastomas.

Journal Article↗
PubMed2004

Signalling activity of beta-catenin targeted to different subcellular compartments.

Beta-catenin plays a dual role as an adhesion molecule in adherens junctions at the plasma membrane and as a key intermediate in the canonical Wnt signalling pathway. The cytosolic soluble pool of beta-catenin, involved in the transmission of the Wnt signal, is normally subjected to rapid protein degradation. On activation of the Wnt cascade, beta-catenin becomes stabilized and then translocates into the nucleus where it co-activates transcription factors of the TCF (T-cell factor)/LEF (lymphoid enhancer factor) family. The expression of plasma membrane-targeted forms of beta-catenin has been shown to also activate TCF/LEF-dependent transcription and different mechanisms have been put forward. In the present study, we have undertaken a systematic analysis of the signalling capability of non-degradable forms of beta-catenin targeted to different cellular compartments. beta-Catenin targeted to the plasma membrane activated transcription to a greater extent compared with non-targeted beta-catenin, and led to a marked stabilization of cytosolic soluble beta-catenin. These effects were independent of the competition with endogenous beta-catenin for binding to E-cadherin at the plasma membrane, since targeting non-degradable beta-catenin to other cellular compartments, i.e. the outer mitochondrial membrane and the endoplasmic reticulum membrane, also resulted in the accumulation of cytosolic wild-type beta-catenin and activation of beta-catenin-dependent signalling. In contrast, nuclear-targeted beta-catenin was without significant effect on cytosolic wild-type beta-catenin and did not activate transcription. Our results suggest that cytosolic accumulation of beta-catenin is a prerequisite for the activation of TCF/LEF-dependent transcription in the nucleus.

Cadherins↗
PubMed2005

Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells.

Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21(cip-1/waf-1). Furthermore, valproic acid inhibits GSK3beta by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia.

Animals↗
PubMed2006

Topological and functional discovery in a gene coexpression meta-network of gastric cancer.

Gastric cancer is a leading cause of global cancer mortality, but comparatively little is known about the cellular pathways regulating different aspects of the gastric cancer phenotype. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we assembled and systematically analyzed a consensus gene coexpression meta-network of gastric cancer incorporating >300 tissue samples from four independent patient populations (the "gastrome"). We find that the gastrome exhibits a hierarchical scale-free architecture, with an internal structure comprising multiple deeply embedded modules associated with diverse cellular functions. Individual modules display distinct subtopologies, with some (cellular proliferation) being integrated within the primary network, and others (ribosomal biosynthesis) being relatively isolated. One module associated with intestinal differentiation exhibited a remarkably high degree of autonomy, raising the possibility that its specific topological features may contribute towards the frequent occurrence of intestinal metaplasia in gastric cancer. At the single-gene level, we discovered a novel conserved interaction between the PLA2G2A prognostic marker and the EphB2 receptor, and used tissue microarrays to validate the PLA2G2A/EphB2 association. Finally, because EphB2 is a known target of the Wnt signaling pathway, we tested and provide evidence that the Wnt pathway may also similarly regulate PLA2G2A. Many of these findings were not discernible by studying the single patient populations in isolation. Thus, besides enhancing our knowledge of gastric cancer, our results show the broad utility of applying meta-analytic approaches to genome-wide data for the purposes of biological discovery.

Cluster Analysis↗
PubMed2001

Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia.

Angiogenesis is not restricted to advanced stages of tumor development but is also observed in benign precursor lesions. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, but the genetic mechanisms controlling its expression in premalignant lesions are poorly described. The Wnt signaling pathway, which is commonly mutated in benign colonic adenomas, was found to strongly up-regulate VEGF. A T-cell factor-4-binding element at -805 bp in the VEGF promoter is an important mediator of this effect. Signaling through the K-ras oncogene, also frequently mutated in benign colonic polyps, up-regulated VEGF in a phosphatidylinositol 3-kinase-dependent manner. Furthermore, K-ras activation appeared to enhance Wnt signaling, which suggests a unique interaction between these two pathways. These studies thus identify VEGF as a novel target of the Wnt pathway in early colonic neoplasia and serve to underscore the importance of angiogenesis in premalignant disease.

Androstadienes↗
PubMed2004

Characterization and functional analysis of the murine Frat2 gene.

The Frat1 proto-oncogene was first identified as a gene contributing to tumor progression in T-cell lymphomas induced by retroviral insertional mutagenesis with the Moloney murine leukemia virus. The biological function of Frat remained elusive until its Xenopus homologue GBP was isolated as a glycogen synthase kinase 3 (GSK3)-binding protein and was shown to be an essential component of the maternal Wnt-signaling pathway. To date two Frat homologues have been described in the mouse, Frat1 and Frat3. The proteins encoded by these two genes are 84% identical. Here we describe the cloning and characterization of a third murine Frat homologue, Frat2, which is the mouse ortholog of human FRAT2. Frat1 and Frat2 are juxtaposed on chromosome 19 in a chromosomal organization conserved between man and mouse. We show that Frat1 and Frat2 are phosphorylated, which is the first evidence that these proteins are subject to posttranslational modification. Like Frat1, Frat2 is able to bind to GSK3beta. However, a side-by-side comparison of the murine Frat proteins for their capacity to induce signaling through beta-catenin/T-cell factor reveals that Frat2 is a less potent activator of the canonical Wnt pathway. Frat2 protein accumulates to higher levels upon transfection into 293T cells than either Frat1 or Frat3. Thus, whereas Frat1 may be a core component of canonical Wnt-signaling, Frat2 might very well be part of a divergent intracellular GSK3beta pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Wnt-1-inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis.

OBJECTIVE: To determine whether Wnt-1-inducible signaling pathway protein 3 (WISP3) polymorphisms are associated with susceptibility to juvenile idiopathic arthritis (JIA). METHODS: The exons and the intron/exon boundaries of the WISP3 gene were mutation-screened by denaturing high-performance liquid chromatography in 86 patients with polyarticular-course JIA (>/=5 joints affected) and 15 controls. Seven single-nucleotide polymorphisms (SNPs) were genotyped, using allelic discrimination, in a case-control study. Initially, 159 patients with polyarticular-course JIA and 263 controls were studied, followed by study of a replication cohort of 181 patients with polyarticular-course JIA and 355 controls. Available parents of patients with polyarticular-course JIA were also genotyped. Finally, other JIA subgroups were studied (initial cohort, n = 218; replication cohort, n = 213). Single-point and haplotype analysis was carried out. RESULTS: Positive association with SNP WISP3*G84A was observed and replicated in 2 cohorts of patients with polyarticular-course JIA. Specifically, homozygosity of the mutant allele (WISP3*84AA) conferred a 2-fold increased risk of disease susceptibility (for the initial cohort, odds ratio [OR] 2.1, 95% confidence interval [95% CI] 1.1-4.2, P = 0.03; for the replication cohort, OR 2.0, 95% CI 1.0-4.3, P = 0.05). Strong linkage disequilibrium was observed between SNPs; however, no haplotypic effect of an order of magnitude greater than the single-point WISP3*G84A association was observed. Using the transmission disequilibrium test, a trend toward overtransmission of the WISP3*84A allele was observed in patients with polyarticular-course JIA. No association of any WISP3 polymorphism was observed in the other JIA subgroups. CONCLUSION: Association and replication of a polymorphism within the first intron of the WISP3 gene have been shown in patients with polyarticular-course JIA. The functional significance of the WISP3*G84A SNP is being determined.

Arthritis, Juvenile↗
PubMed2006

WNT antagonist, SFRP1, is Hedgehog signaling target.

Hedgehog and WNT signaling pathways network together during embryogenesis and carcinogenesis. Hedgehog signaling in intestinal epithelium represses canonical WNT signaling to restrict expression of WNT target genes to stem or progenitor cells; however, the mechanism remains unclear. The Hedgehog signal is transduced to GLI family transcription factors though Patched receptor, Smoothened signal transducer, and other signaling components, such as KIF27, KIF7, STK36, SUFU, and DZIP1. Here, we searched for the GLI-binding site within the promoter region of genes encoding secreted-type WNT signal inhibitors, including SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, and WIF1. The GLI-binding site was identified within the human SFRP1 promoter based on bioinformatics and human intelligence. The chimpanzee SFRP1 gene was identified within the NW_110515.1 genome sequence. The GLI-binding site of the human SFRP1 promoter was conserved in chimpanzee SFRP1, mouse Sfrp1, and rat Sfrp1 promoters. SFRP1 is the evolutionarily conserved target of the Hedgehog-GLI signaling pathway. Expression domain analyses based on text mining revealed that Indian Hedgehog (IHH), SFRP1, and WNT6 are expressed in differentiated intestinal epithelial cells, mesenchymal cells, and stem/progenitor cells, respectively. Hedgehog is secreted from differentiated epithelial cells to induce SFRP1 expression in mesenchymal cells, which keeps differentiated epithelial cells away from the effects of canonical WNT signaling. These facts indicate that SFRP1 is the Hedgehog target to confine canonical WNT signaling within stem or progenitor cells. Therefore, epigenetic CpG hypermethylation of the SFRP1 promoter during chronic persistent inflammation and aging leads to the occurrence of gastrointestinal cancers, such as colorectal cancer and gastric cancer, through the breakdown of Hedgehog-dependent WNT signal inhibition.

Animals↗
PubMed2002

Wnt signaling in the vasculature.

The Wnt signaling pathway regulates normal development as well as a variety of pathologies. Studies of the Wnt pathway have focused largely on very early development and on tumorigenesis. Recent observations point to a role for Wnt signaling in vessel development and pathology. Although not yet investigated systematically, several Wnt ligands have been demonstrated to be expressed in the cells of blood vessels in vivo and in vitro, including Wnt-2, -5a, -7a and -10b. Mice deficient for Wnt-2 display vascular abnormalities including defective placental vasculature. Wnt receptors, called frizzled (Fz), are also expressed by vascular cells in culture and in situ. Of the 10 murine Fz identified to date, Fz-1, -2, -3, and -5 have been demonstrated in endothelial and vascular smooth muscle cells; mice deficient for Fz-5 display vascular abnormalities and are embryonic lethal. Two soluble, naturally occurring Wnt antagonists, frizzled-related proteins (FRP)-1 and -3, are also expressed by vascular cells. Stabilization of the downstream signaling component beta-catenin in blood vessels has been demonstrated in several developmental and pathologic states, further supporting the idea that Wnt signaling plays an important regulatory role in the vasculature.

Animals↗
PubMed2005

Wnt2 as a new therapeutic target in malignant pleural mesothelioma.

Malignant mesothelioma of the pleura (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. A better understanding of its pathogenesis is essential to developing alternative therapeutic strategies. We previously demonstrated that the Wnt signaling pathway is activated in MPM through the overexpression of disheveled proteins. To extend our knowledge of Wnt signaling activation in MPM, we performed Wnt-specific microarrays in normal pleura and MPM. We found that the most common event in MPM was the upregulation of Wnt2. We inhibited Wnt2 by siRNA and a monoclonal anti-Wnt2 antibody and analyzed their effects on apoptosis and downstream signaling effectors. We then assessed the antiproliferative effects of the Wnt2 antibody and Alimta, one of the current standard treatments of MPM. We confirmed Wnt2 overexpression at the mRNA and protein level in MPM cell lines and tissues. We then demonstrated that inhibition of Wnt2 by siRNA or a monoclonal antibody induces programmed cell death in MPM cells. We next analyzed the effects of the anti-Wnt2 antibody and of Alimta on MPM cell proliferation. We found that although Wnt2 antibody by itself had less antiproliferative potency than Alimta, the two in combination had substantially more activity than Alimta alone. We thus propose that inhibition of Wnt2 is of therapeutic interest in the development of more effective treatments for MPM.

Antibodies, Monoclonal↗
PubMed2002

Characterisation of the phosphorylation of beta-catenin at the GSK-3 priming site Ser45.

Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of beta-catenin. In the absence of a Wnt signal, beta-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in beta-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of three of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has recently been shown that the GSK-3 dependent phosphorylation of beta-catenin requires prior priming through phosphorylation of Ser45. However, it is not known whether phosphorylation of Ser45 is carried out by GSK-3 itself or by an alternative kinase. In this study, the phosphorylation of beta-catenin at Ser45 was characterised using a phospho-specific antibody. GSK-3beta was found to be unable to phosphorylate beta-catenin at Ser45 in vitro and in intact cells. However, inhibition of GSK-3 in intact cells reduced Ser45 phosphorylation, suggesting that GSK-3 kinase activity is required for the phosphorylation event. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1varepsilon, a known positive regulator of Wnt signalling, as overexpression of this kinase leads to decreased phosphorylation levels. In conclusion, phosphorylation of beta-catenin at the GSK-3 priming site Ser45 is not mediated by GSK-3 itself, but by an alternative kinase, indicating that beta-catenin is not an unprimed substrate for GSK-3 in vivo. Priming of GSK-3 dependent phosphorylation of beta-catenin by a different kinase could have important implications for the regulation of Wnt signalling.

Amino Acid Substitution↗
PubMed2002

Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons.

Valproate (VPA) and lithium have been used for many years in the treatment of manic depression. However, their mechanisms of action remain poorly understood. Recent studies suggest that lithium and VPA inhibit GSK-3beta, a serine/threonine kinase involved in the insulin and WNT signaling pathways. Inhibition of GSK-3beta by high concentrations of lithium has been shown to mimic WNT-7a signaling by inducing axonal remodeling and clustering of synapsin I in developing neurons. Here we have compared the effect of therapeutic concentrations of lithium and VPA during neuronal maturation. VPA and, to a lesser extent, lithium induce clustering of synapsin I. In addition, lithium and VPA induce similar changes in the morphology of axons by increasing growth cone size, spreading, and branching. More importantly, both mood stabilizers decrease the level of MAP-1B-P, a GSK-3beta-phosphorylated form of MAP-1B in developing neurons, suggesting that therapeutic concentrations of these mood stabilizers inhibit GSK-3beta. In vitro kinase assays show that therapeutic concentrations of VPA do not inhibit GSK-3beta but that therapeutic concentrations of lithium partially inhibit GSK-3beta activity. Our results support the idea that both mood stabilizers inhibit GSK-3beta in developing neurons through different pathways. Lithium directly inhibits GSK-3beta in contrast to VPA, which inhibits GSK-3beta indirectly by an as-yet-unknown pathway. These findings may have important implications for the development of new strategies to treat bipolar disorders.

Animals↗
PubMed2006

Expression of sFRP-4 and beta-catenin in human colorectal carcinoma.

Alterations to the Wnt signalling pathway occur in the majority of colorectal cancers and result in abnormal accumulation of beta-catenin. The secreted frizzled related proteins (sFRPs) are antagonists that bind Wnt and inhibit signalling along this pathway. We investigated expression of the sFRP family member, sFRP-4, and beta-catenin in 1,044 human colorectal carcinomas using tissue microarrays and immunohistochemistry. Both proteins showed markedly increased expression levels in tumors compared to normal mucosa, but no significant associations with pathological features or with patient outcome. sFRP-4 was co-expressed with beta-catenin, p53, and COX-2, while the absence of beta-catenin expression was strongly associated with loss of expression of the MLH1 mismatch repair gene. In contrast to other sFRP family members, sFRP-4 expression appears to be upregulated in colorectal carcinoma.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Wnt signaling in breast cancer: have we come full circle?

Since the original identification of Wnt1 as a mammary oncogene in mouse mammary tumor virus infected mice, questions have been asked about its relevance to human breast cancer. Wnt1 is now known to be one of a large family of Wnt genes encoding structurally similar secreted signaling proteins, several of which are functionally redundant. The principal intracellular signaling pathway activated by these proteins has been elucidated in recent years. Components of this pathway include proto-oncogene products, such as beta-catenin, and tumor suppressor proteins such as APC. Although WNT1 itself has not been implicated in human breast neoplasms, it has been reported that other WNT genes are sometimes overexpressed in human breast cancer and there is growing evidence that downstream components of the Wnt signaling pathway are activated in a significant proportion of breast tumors.

Animals↗
PubMed2005

Nuclear beta-catenin expression is rare and its potential association with short survival in colorectal signet-ring cell carcinoma.

Colorectal signet-ring cell carcinoma (SRCC) is a rare cancer and the prognosis is usually very poor. The biologic pathways involved in its oncogenesis are unknown. beta-catenin, a key target in the Wnt-signaling pathway, is recognized to play an important role in the carcinogenesis in conventional colorectal carcinoma. This study explores the involvement of Wnt-signaling molecules beta-catenin and cyclin D1, cell cycle regulators cyclin D3, proliferative index Ki-67, apoptotic index, and angiogenic indicator CD31 in 20 colorectal SRCC paraffin-embedded specimens. Results showed that there were 2 specimens with nuclear beta-catenin and higher expression of cyclin D1 than the remaining 18 specimens. Surprisingly, those 2 patients had a much shorter survival of 6 months than the remaining 15 patients, who had around 24 months. Moreover, all colorectal SRCC specimens had an overexpression of cyclin D1, cyclin D3, and Ki-67, as well as much more angiogenesis and apoptosis than adjacent normal epithelial tissues. The authors make the preliminary comment that nuclear beta-catenin is a rare phenomenon in colorectal SRCC, but the involvement of it may indicate a worse prognosis with shorter survival than colorectal SRCC without nuclear beta-catenin expression. Besides, overexpression of cyclin D1, cyclin D3, Ki-67, and increased angiogenesis and apoptosis may play a vital role in promoting colorectal SRCC development.

Apoptosis↗
PubMed2002

Wnt-signaling and skeletogenesis.

Members of the Wnt gene family, encoding secreted cystein-rich glycoproteins, have been isolated from a variety of organisms. They serve as important developmental signaling molecules and have been implicated to play crucial roles in such diverse processes as cancer, organogenesis and pattern formation. Experiments by Zakany and Duboule, and Rudnicki and Brown have suggested a role for Wnt molecules in negatively regulating chondrogenesis. However, neither of the two Wnt genes used in these studies is endogenously expressed in chondrogenic regions. We and others have found that in the chick limb at least four members of the Wnt gene family, Wnt-4, Wnt-5a, Wnt-5b, and Wnt-14, are expressed in defined regions of the developing chondrogenic elements. With the exception of Wnt-5b, which is expressed in perichondrial cells and prehypertrophic chondrocytes, the expression of the three other Wnt genes is restricted to the perichondrium surrounding the cartilage element. Viral misexpression studies in the chick suggested that Wnt-4 acts as a positive signal originating from the joint region and when misexpressed accelerates chondrocyte maturation, while Wnt-5a and Wnt-5b both negatively regulate chondrocyte maturation. We have further shown that they utilize different signaling pathways; while Wnt-4 signals through the canonical Wnt-pathway, Wnt-5a and Wnt-5b do not. Interestingly, the delay in chondrocyte maturation due to Wnt-5a misexpression is associated with an up regulation of Wnt-5b expression in the prehypertropic chondrocytes. Concomitantly, Wnt-5b misexpression also delays chondrocyte maturation. However, preliminary studies suggest that the two Wnt genes affect different steps in the maturation process. Wnt signaling, however, is not only regulating chondrogenesis but is also involved in the segmentation process of the appendicular skeleton. Localized misexpression of the fourth Wnt gene, Wnt-14, which is expressed early in the presumptive joint region, induces morphological and molecular changes indicative of an early joint interzone, suggesting that Wnt-14 plays a pivotal role in the induction of the joint interzone.

Journal Article↗
PubMed2003

The signals that drive kidney development: a view from the fly eye.

PURPOSE OF REVIEW: Development of the mammalian kidney is a complex process involving numerous signals and signaling pathways. Other complex tissues have benefited enormously from studies in lower, simpler organisms. The present review provides an update on what we have learned from the fruitfly Drosophila melanogaster, and argues that Drosophila is an important but under-utilized organism for study of renal development. RECENT FINDINGS: The Malpighian tubules provide renal function to the fly. These require a number of signaling pathways for their development that are also seen in vertebrate kidney development, including the Notch, Ras, and Wnt signaling pathways, as well as nuclear factors such as Krüppel and Cut/Cux-1. Many of these factors are shared between early Malpighian tubule development and ureteric bud formation. The Ret signaling receptor, which is central to mammalian renal development, is poorly understood in flies, although its expression pattern is intriguing. Surprisingly, other signaling factors such as Neph-1, Pax2, and Wilms' tumor suppressor-1 appear to work within later fly retinal development, providing a surprising link between these two disparate tissues. SUMMARY: Drosophila offers a powerful palate of tools for dissecting developmental processes. Importantly, these tools can often be examined at the level of single cells, permitting us to address issues of differentiation with high resolution. If we are to take full advantage of Drosophila, however, then we must target specific issues and gain a better understanding of the details of Malpighian tubule development.

Animals↗
PubMed2004

Wnt proteins in mammary development and cancer.

Secreted proteins of the Wnt family play widespread roles in the regulation of embryonic development, and aberrant activation of the canonical Wnt/beta-catenin pathway is one of the most frequent signaling abnormalities known in human cancer. While the consequences of Wnt signaling in development are diverse at the cellular level, they are often concerned with cell fate determination. Recent data also indicate that Wnt proteins influence the self-renewal of stem cells in certain tissues. In the mammary gland, Wnt signals are strongly implicated in initial development of the mammary rudiments, and in the ductal branching and alveolar morphogenesis that occurs during pregnancy. Transgenic expression of Wnt1 or Wnt10b in the mouse mammary gland leads to lobuloalveolar hyperplasia with a major risk of progression to carcinoma. Recent evidence suggests that this phenotype is associated with expansion of a multipotent progenitor cell population. In human breast cancer, evidence of beta-catenin accumulation implies that the canonical Wnt signaling pathway is active in over 50% of carcinomas. However, specific mutations that might account for this activation of signaling have not yet been identified.

Breast↗