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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2012

01-11-2012 | Preclinical study

E-cadherin promotor methylation and mutation are inversely related to motility capacity of breast cancer cells

Authors: Remco van Horssen, Antoinette Hollestelle, Joost A. P. Rens, Alexander M. M. Eggermont, Mieke Schutte, Timo L. M. ten Hagen

Published in: Breast Cancer Research and Treatment | Issue 2/2012

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Abstract

Inactivation of the tumor suppressor E-cadherin is an important event during breast tumorigenesis, as its decreased expression is linked to aggressiveness and metastasis. However, the relationship between the different modes of E-cadherin inactivation (mutation versus promotor hypermethylation) and breast cancer cell behavior is incompletely understood. The high correlation between E-cadherin inactivation status and cell morphology in vitro suggests different biological roles for the two inactivation modes during breast tumorigenesis. Because E-cadherin has been linked to cell invasion and metastasis, and cell motility is a crucial prerequisite to form metastases, we here compared the cell motility capacities of breast cancer cell lines with known E-cadherin status. Using barrier migration assays and time-lapse microscopy, we analyzed the migratory capacity of nine well-characterized human breast cancer cell lines (MDA-MB-231, MCF-7, T47D, BT549, MPE600, CAMA-1, SUM159PT, SUM52PE, and SK-BR-3). This subset was chosen based on E-cadherin gene status (wild-type, mutated, and promotor hypermethylated): three cell lines of each group. In addition, cell proliferation assays were performed for all conditions, to dissect migratory from proliferative effects. In this study, we demonstrate an overt association between the mode of E-cadherin inactivation and cell migration. Promotor hypermethylated E-cadherin cell lines showed a higher migration capacity, while cell lines with mutated E-cadherin were less motile compared to wild-type E-cadherin cell lines. Migration induction by fibronectin and basic fibroblast growth factor did not alter the cell motility association differences. Cell proliferation assays showed that the associations found were not caused by proliferation differences. Inhibition and overexpression of E-cadherin as well as DNA demethylation confirmed the relationship between E-cadherin and breast cancer cell motility. Our results demonstrate an association between the mode of E-cadherin inactivation and migration of breast cancer cells, which justifies more detailed research on the role of E-cadherin inactivation in cell migration and metastasis.
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Literature
1.
Condeelis J, Segall JE (2003) Intravital imaging of cell movement in tumours. Nat Rev Cancer 3(12):921–930PubMedCrossRef
2.
Yamaguchi H, Wyckoff J, Condeelis J (2005) Cell migration in tumors. Curr Opin Cell Biol 17(5):559–564PubMedCrossRef
3.
Wang W, Goswami S, Sahai E, Wyckoff JB, Segall JE, Condeelis JS (2005) Tumor cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol 15(3):138–145PubMedCrossRef
4.
5.
Kemler R (1993) From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet 9(9):317–321PubMedCrossRef
6.
Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI (2005) Alpha-catenin is a molecular switch that binds E-cadherin–beta-catenin and regulates actin-filament assembly. Cell 123(5):903–915PubMedCrossRef
7.
Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ (2005) Deconstructing the cadherin–catenin–actin complex. Cell 123(5):889–901PubMedCrossRef
8.
Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W (1991) E-cadherin-mediated cell–cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113(1):173–185PubMedCrossRef
9.
Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66(1):107–119PubMedCrossRef
10.
Siitonen SM, Kononen JT, Helin HJ, Rantala IS, Holli KA, Isola JJ (1996) Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol 105(4):394–402PubMed
11.
12.
Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392(6674):402–405. doi:10.​1038/​32918 PubMedCrossRef
13.
Gayther SA, Gorringe KL, Ramus SJ, Huntsman D, Roviello F, Grehan N, Machado JC, Pinto E, Seruca R, Halling K, MacLeod P, Powell SM, Jackson CE, Ponder BA, Caldas C (1998) Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 58(18):4086–4089PubMed
14.
Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C (1996) E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13(9):1919–1925PubMed
15.
Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C, van Roy F (1995) E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J 14(24):6107–6115PubMed
16.
Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Hofler H (1994) E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res 54(14):3845–3852PubMed
17.
Becker KF, Atkinson MJ, Reich U, Huang HH, Nekarda H, Siewert JR, Hofler H (1993) Exon skipping in the E-cadherin gene transcript in metastatic human gastric carcinomas. Hum Mol Genet 2(6):803–804PubMedCrossRef
18.
Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, van Beijnum JR, Griffioen AW, Vink J, Krimpenfort P, Peterse JL, Cardiff RD, Berns A, Jonkers J (2006) Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10(5):437–449. doi:10.​1016/​j.​ccr.​2006.​09.​013 PubMedCrossRef
19.
Hollestelle A, Elstrodt F, Timmermans M, Sieuwerts AM, Klijn JG, Foekens JA, den Bakker MA, Schutte M (2010) Four human breast cancer cell lines with biallelic inactivating alpha-catenin gene mutations. Breast Cancer Res Treat 122(1):125–133. doi:10.​1007/​s10549-009-0545-4 PubMedCrossRef
20.
Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55(22):5195–5199PubMed
21.
22.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593–601. doi:10.​1038/​ncb1722 PubMedCrossRef
23.
Savagner P (2001) Leaving the neighborhood: molecular mechanisms involved during epithelial–mesenchymal transition. BioEssays 23(10):912–923PubMedCrossRef
24.
Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, van Eijk R, Eilers PH, van de WB, Cornelisse CJ, Cleton-Jansen AM (2006) E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer 94(5):661–671PubMed
25.
Van Horssen R, Galjart N, Rens JA, Eggermont AM, ten Hagen TL (2006) Differential effects of matrix and growth factors on endothelial and fibroblast motility: application of a modified cell migration assay. J Cell Biochem 99(6):1536–1552PubMedCrossRef
26.
Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82(13):1107–1112PubMedCrossRef
27.
28.
Hollestelle A, Nagel JH, Smid M, Lam S, Elstrodt F, Wasielewski M, Ng SS, French PJ, Peeters JK, Rozendaal MJ, Riaz M, Koopman DG, Ten Hagen TL, de Leeuw BH, Zwarthoff EC, Teunisse A, van der Spek PJ, Klijn JG, Dinjens WN, Ethier SP, Clevers H, Jochemsen AG, den Bakker MA, Foekens JA, Martens JW, Schutte M (2010) Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat 121(1):53–64. doi:10.​1007/​s10549-009-0460-8 PubMedCrossRef
29.
Sisci D, Aquila S, Middea E, Gentile M, Maggiolini M, Mastroianni F, Montanaro D, Ando S (2004) Fibronectin and type IV collagen activate ERalpha AF-1 by c-Src pathway: effect on breast cancer cell motility. Oncogene 23(55):8920–8930PubMedCrossRef
30.
Friedl P, Alexander S (2011) Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147(5):992–1009PubMedCrossRef
31.
32.
33.
34.
Handschuh G, Candidus S, Luber B, Reich U, Schott C, Oswald S, Becke H, Hutzler P, Birchmeier W, Hofler H, Becker KF (1999) Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility. Oncogene 18(30):4301–4312PubMedCrossRef
35.
Vos CB, Cleton-Jansen AM, Berx G, de Leeuw WJ, ter Haar NT, van Roy F, Cornelisse CJ, Peterse JL, van de Vijver MJ (1997) E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 76(9):1131–1133PubMedCrossRef
36.
Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LF, de Jong D, Van de Vijver MJ, Van’t Veer LJ, Peterse JL (2008) Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol 216(2):141–150. doi:10.​1002/​path.​2407 PubMedCrossRef
37.
38.
van de Wetering M, Barker N, Harkes IC, van der Heyden M, Dijk NJ, Hollestelle A, Klijn JG, Clevers H, Schutte M (2001) Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 61(1):278–284PubMed
39.
Suyama K, Shapiro I, Guttman M, Hazan RB (2002) A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell 2(4):301–314PubMedCrossRef
40.
Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA (2000) Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 148(4):779–790PubMedCrossRef
Metadata
Title
E-cadherin promotor methylation and mutation are inversely related to motility capacity of breast cancer cells
Authors
Remco van Horssen
Antoinette Hollestelle
Joost A. P. Rens
Alexander M. M. Eggermont
Mieke Schutte
Timo L. M. ten Hagen
Publication date
01-11-2012
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-012-2261-8

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