Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma

Milovanović, Tatjana; Planutis, Kestutis; Nguyen, Anthony; Marsh, J. Lawrence; Lin, Fritz; Hope, Christopher; Holcombe, Randall F.

doi:10.3892/ijo.25.5.1337

Cited by 73 publications

(79 citation statements)

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“…Wnt ligands and FZD receptors are expressed in human breast cancer cell lines and primary tumors (30)(31)(32)(33). Multiple negative regulators of Wnt/β-catenin signaling, such as SFRP1, SFRP2, SFRP5, WIF1, DKK1, and DKK3, are down-regulated in many breast tumors (34)(35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

Wang

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

165

119

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Prodigiosin, a natural red pigment produced by numerous bacterial species, has exhibited promising anticancer activity; however, the molecular mechanisms of action of prodigiosin on malignant cells remain unclear. Aberrant activation of the Wnt/β-catenin signaling cascade is associated with numerous human cancers. In this study, we identified prodigiosin as a potent inhibitor of the Wnt/ β-catenin pathway. Prodigiosin blocked Wnt/β-catenin signaling by targeting multiple sites of this pathway, including the lowdensity lipoprotein-receptor-related protein (LRP) 6, Dishevelled (DVL), and glycogen synthase kinase-3β (GSK3β). In breast cancer MDA-MB-231 and MDA-MB-468 cells, nanomolar concentrations of prodigiosin decreased phosphorylation of LRP6, DVL2, and GSK3β and suppressed β-catenin-stimulated Wnt target gene expression, including expression of cyclin D1. In MDA-MB-231 breast cancer xenografts and MMTV-Wnt1 transgenic mice, administration of prodigiosin slowed tumor progression and reduced the expression of phosphorylated LRP6, phosphorylated and unphosphorylated DVL2, Ser9 phosphorylated GSK3β, active β-catenin, and cyclin D1. Through its ability to inhibit Wnt/β-catenin signaling and reduce cyclin D1 levels, prodigiosin could have therapeutic activity in advanced breast cancers.prodigiosin | Wnt/beta-catenin signaling | breast cancer | LRP6 | Dishevelled (DVL)

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Section: Discussionmentioning

confidence: 99%

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

Wang

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

165

119

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“…tandem mass spectrometry (Supplementary Methods), and this pointed to binding of POSTN to Wnt ligands 25 . Using TAP-tag pull-downs, we confirmed interaction between POSTN and Wnt1 and Wnt3A, but found that a known inhibitory ligand of the pathway, DKK1, does not associate with POSTN (Fig.…”

Section: Research Lettermentioning

confidence: 99%

Interactions between cancer stem cells and their niche govern metastatic colonization

Malanchi

Santamaria-Martínez

Susanto

et al. 2011

Nature

1,174

996

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Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps 1 . Although dissemination of tumour cells seems to be an early and frequent event 2 , the successful initiation of metastatic growth, a process termed 'metastatic colonization', is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites 3,4 . Prevalent target sites are characteristic of many tumour entities 5 , suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.We aimed to explore limiting factors that determine metastatic success using the MMTV-PyMT mouse breast cancer model, which spontaneously metastasizes to the lungs 6 . We reasoned that the recently identified cancer stem cells (CSCs, also called tumour-initiating cells), a subset of cancer cells that allow long-term tumour growth and are thought to be responsible for remissions 7,8 , might also be relevant to the development of metastatic disease ( Supplementary Fig. 1). We measured the relative size of the population of CSCs from primary MMTV-PyMT tumours and their pulmonary metastases using the previously established markers CD90 and CD24, which label a subset of the CD24 1 CD29hi or CD241 CD49f hi population used earlier to isolate CSCs and normal mammary gland stem cells 9-13 (Supplementary Fig. 2). This CSC subset accounts for 3 6 2.1% (s.d.) of all tumour cells from both primary tumours and metastases (Fig. 1a). When CD90 1 CD241 CSCs or CD90 1 CD24 1 -depleted non-CSCs are separately isolated from GFP 1 tumours and directly introduced into mice through tail vein injection (GFP, green fluorescent protein), only the CSC population is able to produce lung metastases (Fig. 1b). Moreover, CD90 1 CD241 cells isolated subsequently from pulmonary metastases are again the only tumour cell population that efficiently initiates secondary metastases (Fig. 1c). This is not due to differences in the extravasation capabilities of CSCs an...

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“…In a majority of tumours, aberrant activation of the Wnt/b-catenin is the consequence of APC, Axin or b-catenin gene mutations (Lustig and Behrens, 2003). Moreover, it has been shown that overactivation of the Wnt signalling pathway is due to the overexpression of different FZD receptors in a variety of cancers (Milovanovic et al, 2004;Merle et al, 2005;Ueno et al, 2008). In NB, b-catenin has been shown to be strongly expressed and aberrantly localized in the nucleus in highly aggressive NB cells without MYCN amplification, whereas no b-catenin-specific mutations were identified (Liu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

et al. 2009

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The development of chemoresistance represents a major obstacle in the successful treatment of cancers such as neuroblastoma (NB), a particularly aggressive childhood solid tumour. The mechanisms underlying the chemoresistant phenotype in NB were addressed by gene expression profiling of two doxorubicin (DoxR)-resistant vs sensitive parental cell lines. Not surprisingly, the MDR1 gene was included in the identified upregulated genes, although the highest overexpressed transcript in both cell lines was the frizzled-1 Wnt receptor (FZD1) gene, an essential component of the Wnt/b-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/b-catenin pathway as revealed by nuclear b-catenin translocation and target genes transactivation. Interestingly, specific microadapted short hairpin RNA (shRNAmir)-mediated FZD1 silencing induced parallel strong decrease in the expression of MDR1, another b-catenin target gene, revealing a complex, Wnt/b-catenin-mediated implication of FZD1 in chemoresistance. The significant restoration of drug sensitivity in FZD1-silenced cells confirmed the FZD1-associated chemoresistance. RNA samples from 21 patient tumours (diagnosis and postchemotherapy), showed a highly significant FZD1 and/or MDR1 overexpression after treatment, underlining a role for FZD1-mediated Wnt/b-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/b-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.

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Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma

Cited by 73 publications

References 0 publications

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

Interactions between cancer stem cells and their niche govern metastatic colonization

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

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