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PMID: 18611862 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Slit-2 induces a tumor-suppressive effect by regulating beta-catenin in breast cancer cells.

The Journal of biological chemistry ·Vol. 283 ·No. 39 ·2008-09-26 ·Pages 26624-33

Prasad A, Paruchuri V, Preet A, Latif F, Ganju RK

Abstract

SLIT-2 is considered as a candidate tumor suppressor gene, because it is frequently inactivated in various cancers due to hypermethylation of its promoter region and allelic loss. However, the exact mechanism of its tumor-suppressive effect has not been elucidated. Here, we observed that Slit-2-overexpressing breast cancer cells exhibited decreased proliferation and migration capabilities compared with control cells under in vitro conditions. These results were confirmed in vivo in mouse model systems. Mice injected with MCF-7/Slit-2 cells showed a 60-70% reduction in tumor size compared with mice injected with MCF-7/VC cells both in the absence and presence of estrogen. Upon further elucidation, we observed that Slit-2 mediates the tumor-suppressive effect via a coordinated regulation of the beta-catenin and PI3K signaling pathways and by enhancing beta-catenin/E-cadherin-mediated cell-cell adhesion. Our study for the first time reveals that Slit-2-overexpressing breast cancer cells exhibit tumor suppressor capabilities through the novel mechanism of beta-catenin modulation.

MeSH Terms
Animals Breast Neoplasms/metabolism,pathology Cadherins/biosynthesis Cell Adhesion Cell Line, Tumor DNA Methylation Female Gene Expression Regulation, Neoplastic Humans Intercellular Signaling Peptides and Proteins/biosynthesis Loss of Heterozygosity Mice Mice, Nude Mice, SCID Neoplasm Transplantation Nerve Tissue Proteins/biosynthesis Phosphatidylinositol 3-Kinases Promoter Regions, Genetic Signal Transduction Tumor Suppressor Proteins/biosynthesis beta Catenin/biosynthesis
Chemicals
Cadherins Intercellular Signaling Peptides and Proteins Nerve Tissue Proteins Tumor Suppressor Proteins beta Catenin Phosphatidylinositol 3-Kinases Slit homolog 2 protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Prasad Anil
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA. abailugu@bidmc.harvard.edu
Paruchuri Vikram
Preet Anju
Latif Farida
Ganju Ramesh K
References (63)
63 references, click to expand
  1. Stimulation of MCF-7 tumor progression in athymic nude mice by 17beta-estradiol induces WISP-2/CCN5 expression in xenografts: a novel signaling molecule in hormonal carcinogenesis.
    Oncol Rep. 2005 Mar;13(3):445-8 PMID: 15706414
  2. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance.
    Cell. 1999 Mar 19;96(6):795-806 PMID: 10102268
  3. SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site.
    Dev Cell. 2004 May;6(5):709-17 PMID: 15130495
  4. Robo1/Robo4: differential expression of angiogenic markers in colorectal cancer.
    Oncol Rep. 2006 Jun;15(6):1437-43 PMID: 16685377
  5. Switching repulsion to attraction: changing responses to slit during transition in mesoderm migration.
    Science. 2001 Apr 27;292(5517):737-40 PMID: 11326102
  6. Expression of the vertebrate Slit gene family and their putative receptors, the Robo genes, in the developing murine kidney.
    Mech Dev. 2000 Jun;94(1-2):213-7 PMID: 10842075
  7. Cables links Robo-bound Abl kinase to N-cadherin-bound beta-catenin to mediate Slit-induced modulation of adhesion and transcription.
    Nat Cell Biol. 2007 Aug;9(8):883-92 PMID: 17618275
  8. Inhibition of medulloblastoma cell invasion by Slit.
    Oncogene. 2006 Aug 24;25(37):5103-12 PMID: 16636676
  9. Neuronal repellent Slit2 inhibits dendritic cell migration and the development of immune responses.
    J Immunol. 2003 Dec 15;171(12):6519-26 PMID: 14662852
  10. Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes.
    Curr Opin Genet Dev. 2002 Oct;12(5):583-91 PMID: 12200164
  11. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway.
    Genes Dev. 2002 May 1;16(9):1066-76 PMID: 12000790
  12. Signal transduction: signaling specificity- a complex affair.
    Science. 2001 Jun 29;292(5526):2439-40 PMID: 11431552
  13. Lateral positioning at the dorsal midline: Slit and Roundabout receptors guide Drosophila heart cell migration.
    Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12441-6 PMID: 16888037
  14. Transactivation of vimentin by beta-catenin in human breast cancer cells.
    Cancer Res. 2003 May 15;63(10):2658-64 PMID: 12750294
  15. Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons.
    Cell. 1999 Mar 19;96(6):807-18 PMID: 10102269
  16. Transactivation of MCP-1/CCL2 by beta-catenin/TCF-4 in human breast cancer cells.
    Int J Cancer. 2006 Jan 1;118(1):35-42 PMID: 16003740
  17. Slit and robo: expression patterns in lung development.
    Gene Expr Patterns. 2003 Mar;3(1):13-9 PMID: 12609596
  18. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway.
    Am J Pathol. 1999 Feb;154(2):515-23 PMID: 10027409
  19. Comparative genomics on SLIT1, SLIT2, and SLIT3 orthologs.
    Oncol Rep. 2005 Nov;14(5):1351-5 PMID: 16211308
  20. The mouse SLIT family: secreted ligands for ROBO expressed in patterns that suggest a role in morphogenesis and axon guidance.
    Dev Biol. 1999 Aug 15;212(2):290-306 PMID: 10433822
  21. Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells.
    J Biol Chem. 2004 Mar 5;279(10):9115-24 PMID: 14645233
  22. SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers.
    Cancer Res. 2002 Oct 15;62(20):5874-80 PMID: 12384551
  23. Chemokines and cancer.
    Int J Cancer. 2006 Nov 1;119(9):2026-9 PMID: 16671092
  24. Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching.
    Cell. 1999 Mar 19;96(6):771-84 PMID: 10102266
  25. Potential role of the Slit/Robo signal pathway in angiogenesis.
    Vasc Med. 2006 May;11(2):115-21 PMID: 16886842
  26. Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion.
    Nat Cell Biol. 2002 Oct;4(10):798-805 PMID: 12360290
  27. Assignment of the human slit homologue SLIT2 to human chromosome band 4p15.2.
    Cytogenet Cell Genet. 1999;86(3-4):246-7 PMID: 10575218
  28. Frequent epigenetic inactivation of the SLIT2 gene in gliomas.
    Oncogene. 2003 Jul 17;22(29):4611-6 PMID: 12881718
  29. Short-range and long-range guidance by slit and its Robo receptors. Robo and Robo2 play distinct roles in midline guidance.
    Neuron. 2000 Dec;28(3):753-66 PMID: 11163264
  30. Inadequate lung development and bronchial hyperplasia in mice with a targeted deletion in the Dutt1/Robo1 gene.
    Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15062-6 PMID: 11734623
  31. Cadherin cell adhesion receptors as a morphogenetic regulator.
    Science. 1991 Mar 22;251(5000):1451-5 PMID: 2006419
  32. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes.
    Mol Cell Biol. 1996 May;16(5):2128-34 PMID: 8628279
  33. Crossing the midline: roles and regulation of Robo receptors.
    Neuron. 2000 Dec;28(3):767-77 PMID: 11163265
  34. MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells.
    Mol Ther. 2003 Aug;8(2):207-19 PMID: 12907143
  35. Beta-catenin and Tcfs in mammary development and cancer.
    J Mammary Gland Biol Neoplasia. 2003 Apr;8(2):145-58 PMID: 14635791
  36. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly.
    Science. 1996 May 17;272(5264):1023-6 PMID: 8638126
  37. Binding site for Robo receptors revealed by dissection of the leucine-rich repeat region of Slit.
    EMBO J. 2004 Nov 10;23(22):4406-12 PMID: 15496984
  38. SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma.
    Br J Cancer. 2004 Jan 26;90(2):515-21 PMID: 14735202
  39. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
    Nature. 1999 Apr 1;398(6726):422-6 PMID: 10201372
  40. Chimeric axon guidance receptors: the cytoplasmic domains of slit and netrin receptors specify attraction versus repulsion.
    Cell. 1999 Jun 25;97(7):917-26 PMID: 10399919
  41. Metalloproteinases: role in breast carcinogenesis, invasion and metastasis.
    Breast Cancer Res. 2000;2(4):252-7 PMID: 11250717
  42. Slit is the midline repellent for the robo receptor in Drosophila.
    Cell. 1999 Mar 19;96(6):785-94 PMID: 10102267
  43. The N-terminal leucine-rich regions in Slit are sufficient to repel olfactory bulb axons and subventricular zone neurons.
    J Neurosci. 2001 Mar 1;21(5):1548-56 PMID: 11222645
  44. Changes in gene expression patterns in the ureteric bud and metanephric mesenchyme in models of kidney development.
    Kidney Int. 2003 Dec;64(6):1997-2008 PMID: 14633122
  45. Cadherins and catenins in breast cancer.
    Curr Opin Cell Biol. 2005 Oct;17(5):499-508 PMID: 16107313
  46. The cadherin-catenin adhesion system in signaling and cancer.
    J Clin Invest. 2002 Apr;109(8):987-91 PMID: 11956233
  47. Molecular architecture of adherens junctions.
    Curr Opin Cell Biol. 2001 Oct;13(5):600-3 PMID: 11544029
  48. E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma.
    J Pathol. 1998 Jul;185(3):262-6 PMID: 9771479
  49. Magic roundabout, a tumor endothelial marker: expression and signaling.
    Biochem Biophys Res Commun. 2005 Jul 1;332(2):533-41 PMID: 15894287
  50. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors.
    Oncogene. 1999 May 6;18(18):2883-91 PMID: 10362259
  51. SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells.
    Cancer Res. 2003 Mar 1;63(5):1054-8 PMID: 12615722
  52. Defective E-cadherin/catenin complexes in human cancer.
    Virchows Arch. 2001 Dec;439(6):725-51 PMID: 11787845
  53. Influence of c-myc on the progression of human breast cancer.
    Curr Top Microbiol Immunol. 1996;213 ( Pt 2):267-83 PMID: 9053295
  54. Repellent signaling by Slit requires the leucine-rich repeats.
    J Neurosci. 2001 Jun 15;21(12):4290-8 PMID: 11404414
  55. BRCA1 and E-cadherin promoter hypermethylation and gene inactivation in cancer-association or mechanism?
    J Natl Cancer Inst. 2000 Apr 5;92(7):515-7 PMID: 10749897
  56. Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers.
    Br J Cancer. 2004 Dec 13;91(12):2071-8 PMID: 15534609
  57. Actin dynamics and cell-cell adhesion in epithelia.
    Curr Opin Cell Biol. 2001 Feb;13(1):76-84 PMID: 11163137
  58. Identification of c-MYC as a target of the APC pathway.
    Science. 1998 Sep 4;281(5382):1509-12 PMID: 9727977
  59. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
    Nature. 1995 Dec 21-28;378(6559):785-9 PMID: 8524413
  60. Homozygous deletions at 3p12 in breast and lung cancer.
    Oncogene. 1998 Oct 1;17(13):1723-9 PMID: 9796701
  61. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A.
    Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11960-5 PMID: 11035810
  62. beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer.
    Am J Pathol. 1999 Oct;155(4):1033-8 PMID: 10514384
  63. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity.
    J Biol Chem. 2007 Apr 13;282(15):11221-9 PMID: 17287208
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M800679200
Email
abailugu@bidmc.harvard.edu
Published
2008-09-26
Epub
2008-00-08
Pages
26624-33
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2546548
Subset
IM
Grants
NCI NIH HHS · CA109527 · United States
External Links
PubMed source DOI: 10.1074/jbc.M800679200 PMC Full Text View journal details
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