Wnt-5a/Ca<sup>2+</sup>-Induced NFAT Activity Is Counteracted by Wnt-5a/Yes-Cdc42-Casein Kinase 1α Signaling in Human Mammary Epithelial Cells

Dejmek, Janna; Säfholm, Annette; Nielsen, Christian Kamp; Andersson, Tommy; Leandersson, Karin

doi:10.1128/mcb.02354-05

Cited by 143 publications

(125 citation statements)

References 69 publications

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“…In breast cancer, Wnt-5a has been shown to increase adhesion and to reduce migration of epithelial cells, explaining its link to the metastatic process and patient outcomes (8,9). We have developed a formylated hexapeptide, Foxy-5, capable of mimicking the effects of Wnt-5a on adhesion and migration of breast cancer cells (10).…”

mentioning

confidence: 99%

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

Ford

Ekström

Andersson

2009

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

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One third of all breast cancers are estrogen receptor alpha (ERα) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ERα in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ERα and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERα-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERα expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ERα promoter. Up-regulated ERα could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERα responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ERα expression in an in vivo model of ERα-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERα expression in ERα-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERα-negative breast cancer patients.

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confidence: 99%

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

Ford

Ekström

Andersson

2009

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

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“…Three-dimensional invasion assays were carried out using Matrigel invasion chambers (BD) with 8-m pore size membranes, in a 24-well plate format. Cell invasion was performed as described previously (5). Briefly, cells were resuspended in serum-free media (25,000 cells/well).…”

Section: Methodsmentioning

confidence: 99%

“…Wnt5a has been shown to stimulate increases in intracellular Ca 2ϩ levels in developmental models (3) and mammalian cell lines, including breast and thyroid cancer cells (4)(5)(6), giving rise to the model of a non-canonical Wnt/Ca 2ϩ signaling pathway. Wnt5a-mediated intracellular increases in Ca 2ϩ levels enables the activation of Ca 2ϩ -regulated proteins, such as protein kinase C (PKC) in a context dependent manner, as reviewed recently (7).…”

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confidence: 99%

A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion

Jenei

Sherwood

Howlin

et al. 2009

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

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The influential role of Wnt5a in tumor progression underscores the requirement for developing molecules that can target Wnt5a-mediated cellular responses. In the aggressive skin cancer, melanoma, elevated Wnt5a expression promotes cell motility and drives metastasis. Two approaches can be used to counteract these effects: inhibition of Wnt5a expression or direct blockade of Wnt5a signaling. We have investigated both options in the melanoma cell lines, A2058 and HTB63. Both express Frizzled-5, which has been implicated as the receptor for Wnt5a in melanoma cells. However, only the HTB63 cell line expresses and secretes Wnt5a. In these cells, the cytokine, TGF␤1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGF␤1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGF␤1 was an unsuitable strategy to pursue. We therefore attempted to target Wnt5a signaling directly. Exogenous Wnt5a stimulation of A2058 cells increased adhesion, migration and invasion, all crucial components of tumor metastasis, and the Wnt5a-derived N-butyloxycarbonyl hexapeptide (Met-Asp-Gly-Cys-Glu-Leu; 0.766 kDa) termed Box5, abolished these responses. Box5 also inhibited the basal migration and invasion of Wnt5a-expressing HTB63 melanoma cells. Box5 antagonized the effects of Wnt5a on melanoma cell migration and invasion by directly inhibiting Wnt5a-induced protein kinase C and Ca 2؉ signaling, the latter of which we directly demonstrate to be essential for cell invasion. The Box5 peptide directly inhibits Wnt5a signaling, representing an approach to anti-metastatic therapy for otherwise rapidly progressive melanoma, and for other Wnt5a-stimulated invasive cancers.inhibitory peptide ͉ malignant melanoma ͉ tumor cell invasion W nt ligands comprise a family of 19 human secreted signaling proteins, which coordinate essential processes required for development and maintenance of tissue homeostasis. Misregulation of Wnt signaling can lead to cancer progression (1). The Wnt ligands are secreted glycoproteins that can be divided based on their ability to activate different intracellular signals, in a tissue-dependent manner. One group primarily activates canonical signaling that controls ␤-catenin stability, while the other is loosely described as ␤-catenin-transcriptionally independent (non-canonical Wnt signaling). However, cross-talk between the two signaling networks does exist (2).Wnt5a is in most situations characterized as a non-canonical Wnt ligand that elicits intracellular signals through association with distinct receptors and co-receptors in a cell specific manner. Wnt5a has been shown to stimulate increases in intracellular Ca 2ϩ levels in developmental models (3) and mammalian cell lines, including breast and thyroid cancer cells (4-6), giving rise to the model of a non-canonical Wnt/Ca 2ϩ signaling pathway. Wnt5a-mediated intracellular increases in Ca 2ϩ levels enables the activation of Ca 2ϩ -regulated proteins, such as protein kinase C (PKC) in a context dependent manner, as reviewed recen...

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“…The FGF20, JAG1, DKK1 and WISP1 genes are primary transcriptional targets of the canonical WNT signaling pathway (10)(11)(12)(13)(14). On the other hand, WNT5A signaling through FZD family receptor and ROR2/PTK7/ RYK co-receptor is transduced to a variety of non-canonical WNT signaling cascades, such as the Dishevelled-dependent RHOA/RHOU/RAC/CDC42, the Dishevelled-dependent (15)(16)(17)(18)(19)(20)(21). WNT5A signals are transduced to the canonical WNT signaling cascade for the maintenance of stem and progenitor cells, and to the noncanonical WNT signaling cascades for the control of tissue polarity, cell adhesion, and cell movement (Fig.…”

Section: Wnt5a Signaling Overviewmentioning

confidence: 99%

STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review)

Katoh¹,

Katoh²

2007

Int J Mol Med

120

131

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Abstract. Leukemia inhibitory factor (LIF), oncostatin M, leptin, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine factor 1, interleukin 6 (IL6), interleukin 11 and interleukin 27 activate the gp130-JAK-STAT3 signaling cascade. Here, WNT5A was characterized as the evolutionarily conserved target of the STAT3 signaling cascade based on 11-bp-spaced tandem STAT3-binding sites within intron 4 of human, chimpanzee, cow, mouse and rat WNT5A orthologs. Canonical WNT5A signaling through Frizzled and LRP5/LRP6 receptors activates FGF20, WISP1, MYC and CCND1 transcription for the maintenance of stem/ progenitor cells, while non-canonical WNT5A signaling through Frizzled and ROR2/PTK7/RYK receptors activates the RHOA, JNK, NLK and NFAT signaling cascades for the control of tissue polarity, cell adhesion or movement. LIFinduced Wnt5a activates canonical Wnt signaling in mouse embryonic stem cells for self-renewal. STAT3-induced Wnt5a activates non-canonical Wnt signaling in rat cardiac myocytes for N-cadherin-dependent aggregation. IL6, secreted from epithelial cells or macrophages, induces WNT5A upregulation in mesenchymal cells. WNT5A then activates canonical WNT signaling in epithelial cells. IL6-induced WNT5A activates canonical WNT signaling for autocrine proliferation of human synovial fibroblasts in rheumatoid arthritis. IL-6 signaling is activated during human chronic atrophic gastritis with Helicobacter pylori infection, and aberrant Stat3 signaling activation gives rise to mouse gastric tumors. WNT5A is frequently upregulated in human primary gastric cancer due to tumor-stromal interaction. WNT5A might be downregulated in advanced cancer with poorer prognosis due to genetic alterations compensating WNT5A signaling. Oncogenic WNT5A activates canonical WNT signaling in cancer stem cells for self-renewal, and non-canonical WNT signaling at the tumor-stromal interface for invasion and metastasis. SNP of genes encoding components of the cytokine-induced WNT5A signaling loop is a predicted risk factor for RA and cancer, especially diffuse-type gastric and pancreatic cancer. Humanized anti-IL6 receptor antibody and WNT5A mimetic small-molecule antagonist could be applied to personalized medicine for RA and cancer driven by the IL6-induced WNT5A signaling loop. Contents1. WNT5A signaling overview 2. STAT3-dependent WNT5A upregulation 3. LIF-induced WNT5A signaling loop for embryonic stem cells 4. Leptin-induced WNT5A signaling loop for cardiac myocytes 5. IL6-induced WNT5A signaling loop in rheumatoid arthritis 6. IL6-induced WNT5A signaling loop in chronic inflammation and cancer 7. Perspectives WNT5A signaling overviewWNT5A is a secreted glycoprotein, belonging to the WNT family (1-4). WNT5A signaling through Frizzled (FZD) family receptor and LRP5/LRP6 co-receptor is transduced to the canonical WNT signaling cascade for transcriptional activation of target genes based on the nuclear complex, consisting of TCF/LEF, ß-catenin, BCL9/BCL9L and PYGO1/PYGO2 (5-9). The FGF20, JAG1, DKK1 and WISP1 gen...

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Wnt-5a/Ca²⁺-Induced NFAT Activity Is Counteracted by Wnt-5a/Yes-Cdc42-Casein Kinase 1α Signaling in Human Mammary Epithelial Cells

Cited by 143 publications

References 69 publications

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion

STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review)

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Wnt-5a/Ca2+-Induced NFAT Activity Is Counteracted by Wnt-5a/Yes-Cdc42-Casein Kinase 1α Signaling in Human Mammary Epithelial Cells

Cited by 143 publications

References 69 publications

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion

STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review)

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Wnt-5a/Ca²⁺-Induced NFAT Activity Is Counteracted by Wnt-5a/Yes-Cdc42-Casein Kinase 1α Signaling in Human Mammary Epithelial Cells