Cadherin Junctions in Mammary Tumors

  • Margaret J. Wheelock
  • Alejandro Peralta Soler
  • Karen A. Knudsen


Cadherins are the transmembrane component of adherens junctions found between interacting cells in tissues. The cadherins bind cells to one another in a specific manner and link to the actin cytoskeleton through intracellular catenins. In addition to promoting strong cell-cell adhesion, cadherins appear to initiate and modify intracellular signaling pathways. The loss of E-cadherin function in epithelial cells is thought to be an important step in tumorigenesis. Moreover, anomalous expression of inappropriate cadherins in epithelial cells alters their behavior and may contribute to the tumorigenic phenotype. For breast cancer the decreased expression of E-cadherin alone may have limited value as a prognostic indicator; however, examining the repertoire of cadherins and catenins expressed by tumors may provide useful prognostic information.

Cadherin cancer motility invasion 


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  1. 1.
    M. Takeichi (1990). Cadherins: A molecular family important in selective cell-cell adhesion. Annu. Rev. Biochem. 59:237-252.PubMedGoogle Scholar
  2. 2.
    O. W. Blaschuk, S. Munro, and R. Farookhi (1995). Cadherins, steroids and cancer. Endocrine 3:83-89.Google Scholar
  3. 3.
    M. J. Wheelock, K. A. Knudsen, and K. R. Johnson (1996). Membrane-cytoskeleton interactions with cadherin cell adhesion proteins; roles of catenins as linker proteins. Current Topics in Membranes 43:169-185.Google Scholar
  4. 4.
    K. A. Knudsen, C. Frankowsky, K. R. Johnson, and M. J. Wheelock (1998). A role for cadherins in cellular signaling and differentiation. J. Cell. Biochem. S 30/31:168-176.Google Scholar
  5. 5.
    K. R. Johnson, M. J. Wheelock, and M. Takeichi (1999). Cadherins. In T. Kreis and R. Vale (eds.), Guidebook to the Extracellular Matrix, Anchor, and Adhesion Proteins, Oxford University Press, Oxford, pp. 141-149.Google Scholar
  6. 6.
    W.-S. Shan, H. Tanaka, G. R. Phillips, K. Arndt, M. Yoshida, D. R. Colman, and L. Shapiro (2000). Functional cisheterodimers of N-and R-cadherins. J. Cell Biol. 148:579-590.PubMedGoogle Scholar
  7. 7.
    F. S. Walsh and P. Doherty (1997). Neural cell adhesion molecules of the immunoglobulin super family: Role in axonal growth and guidance. Annu. Rev. Cell Biol. 13:425-456.Google Scholar
  8. 8.
    M. T. Nieman, R. S. Prudoff, K. R. Johnson, and M. J. Wheelock (1999). N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J. Cell Biol. 147:631-643.PubMedGoogle Scholar
  9. 9.
    R. B. Hazan, G. R. Phillips, R. F. Qiao, L. Norton, and S. A. Aaronson (2000). Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J. Cell Biol. 148:779-790.PubMedGoogle Scholar
  10. 10.
    J. K. Wahl., P. A. Sacco, T. M. McGranahan, L. Sauppé, M. J. Wheelock, and K. R. Johnson (1996). Plakoglobin domains that define its association with the desmosomal cadherins and the classical cadherins: Identification of unique and shared domains. J. Cell Sci. 109:1043-1054.Google Scholar
  11. 11.
    J. E. Nieset, A. R. Redfield, F. Jin, K. A. Knudsen, K. R. Johnson, and M. J. Wheelock (1997). Characterization of the interactions of α-catenin with α-actinin and βcatenin/ plakoglobin. J. Cell Sci. 110:1013-1022.PubMedGoogle Scholar
  12. 12.
    J. M. Daniel, and A. B. Reynolds (1997). Tyrosine phosphorylation and cadherin/catenin function. BioEssays 19:883-891.PubMedGoogle Scholar
  13. 13.
    J. R. Miller, A. M. Hocking, J. D. Brown, and R. T. Moon (1999). Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2C pathways. Oncogene 18:7860-7872.PubMedGoogle Scholar
  14. 14.
    K. M. Cadigan and R. Nusse (1997). Wnt signaling: A common theme in animal development. Genes Dev. 11:3286-3305.PubMedGoogle Scholar
  15. 15.
    P. Polakis, M. Hart, and B. Rubinfeld (1999). Defects in the regulation of beta-catenin in colorectal cancer. Adv. Exp. Med. Biol. 470:23-32.PubMedGoogle Scholar
  16. 16.
    P. J. Morin. β-catenin signaling and cancer (1999). BioEssays 21:1021-1030.PubMedGoogle Scholar
  17. 17.
    S. Aono, S. Nakagawa, A. B. Reynolds, and M. Takeichi (1999). p120(ctn) acts as an inhibitory regulator of cadherin function in colon carcinoma cells. J. Cell Biol. 145:551-562.PubMedGoogle Scholar
  18. 18.
    T. Ohkubo and M. Ozawa (1999). p120(ctn) binds to the membrane-proximal region of the E-cadherin cytoplasmic domain and is involved in modulation of adhesion activity. J. Biol. Chem. 274:21409-21415.PubMedGoogle Scholar
  19. 19.
    M. A. Thoreson, P. Z. Anastasiadis, J. M. Daniel, R. C. Ireton, M. J. Wheelock, K. R. Johnson, D. K. Hummingbird, and A. B. Reynolds (2000). Selective uncoupling of p120(ctn) from Ecadherin disrupts strong adhesion. J. Cell Biol. 148:189-202.PubMedGoogle Scholar
  20. 20.
    P. Z. Anastasiadis, S. Y. Moon, M. A. Thoreson, D. J. Mariner, H. C. Crawford, Y. Zheng, and A. B. Reynolds (2000). Inhibition of RhoA by p120 catenin. Nat. Cell Biol. 9:637-644.Google Scholar
  21. 21.
    N. K. Noren, B. P. Liu, K. Burridge, and B. Kreft (2000). p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J. Cell Biol. 150:567-580.PubMedGoogle Scholar
  22. 22.
    S. M. Brady-Kalnay and N. K. Tonks (1995). Protein tyrosine phosphatases as adhesion receptors. Curr. Opin. Cell Biol. 7:650-657.PubMedGoogle Scholar
  23. 23.
    P. Guilford (1999). E-cadherin down-regulation in cancer: Fuel on the fire? Molecular Medicine Today 5:172-177.PubMedGoogle Scholar
  24. 24.
    J. Behrens (1999). Cadherins and catenins: Role in signal transduction and tumor progression. Cancer and Metastasis Reviews 18:15-30.PubMedGoogle Scholar
  25. 25.
    M. A. El-Bahrawy, and M. Pignatelli (1998). E-cadherin and catenins: Molecules with versatile roles in normal and neoplastic epithelial cell biology. Microscopy Research and Technique 43:224-232.PubMedGoogle Scholar
  26. 26.
    A.-K. Perl, P. Wilgenbus, U. Dahl, H. Semb, and G. Christofori (1998). A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392:190-193.PubMedGoogle Scholar
  27. 27.
    G. Berx, K.-F. Becker, H. Höfler, and F. van Roy (1998). Mutations of the human E-cadherin (CDH1) gene. Human Mutation 12:226-237.PubMedGoogle Scholar
  28. 28.
    F. Nollet, G., Berx, and F. van Roy (1999). The role of the E-cadherin/catenin adhesion complex in the development and progression of cancer. Mol. Bell Biol. Res. Comm. 2:77-85.Google Scholar
  29. 29.
    M. J. Pishvaian, C. M. Feltes, P. Thompson, M. J. Bussemakers, J. A. Schalken, and S. W. Byers (1999). Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Res. 59:947-952.PubMedGoogle Scholar
  30. 30.
    S. Islam, T. E. Carey, G. T. Wolf, M. J. Wheelock, and K. R. Johnson (1996). Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion. J. Cell Biol. 135:1643-1654.PubMedGoogle Scholar
  31. 31.
    J.-B. Kim, S. Islam, Y. J. Kim, R. S. Prudoff, K. M. Sass, M. J. Wheelock, and K. R. Johnson (2000). N-cadherin extracellular repeat 4 mediates epithelial to mesenchymal transition and increased motility. J. Cell Biol. 151:1193-1205.PubMedGoogle Scholar
  32. 32.
    A. Peralta Soler, K. A. Knudsen, M.-C. Jaurand, K. R. Johnson, M. J. Wheelock, A. J. P. Klein-Szanto, and H. Salazar (1995). The differential expression of N-cadherin and E-cadherin distinguishes pleural mesotheliomas from lung adenocarcinomas. Human Pathology 26:1363-1369.PubMedGoogle Scholar
  33. 33.
    R. B. Hazan, L. Kang, B. P. Whooley, and P. I. Borgen (1997). N-cadherin promotes adhesion between invasive breast cancer cells and the stroma. Cell Adhes. Commun. 4:399-411.PubMedGoogle Scholar
  34. 34.
    A. S. T. Wong, S. L. Maines-Bandiera, B. Rosen, M. J. Wheelock, K. R. Johnson, P. C. K. Leung, C. D. Roskelley, and N. Auersperg (1999). Constitutive and conditional cadherin expression in cultured human ovarian surface epithelium: Influence of family history of ovarian cancer. Int. J. Cancer 81:180-188.PubMedGoogle Scholar
  35. 35.
    M. Katayama, S. Hirai, K. Kamihagi, K. Nakagawa, M. Yasumoto, and I. Kato (1994). Soluble E-cadherin fragments increased in circulation of cancer patients. Br. J. Cancer 69:580-585.PubMedGoogle Scholar
  36. 36.
    K. A. Knudsen, Y. L. Chen, K. R. Johnson, M. J. Wheelock, A. A. Keshgegian, and A. Peralta Soler (2000). Lack of correlation between serum levels of E-and P-cadherin fragments and the presence of breast cancer. Human Pathology 31:961-965.PubMedGoogle Scholar
  37. 37.
    S. Shirahama, F. Furukawa, H. Wakita, and M. Takigawa (1996). E-and P-cadherin expression in tumor tissues and soluble E-cadherin levels in sera of patients with skin cancer. J. Dermatol. Sci. 13:30-36.PubMedGoogle Scholar
  38. 38.
    S. Hiraguri, T. Godfrey, H. Nakamura, J. Graff, C. Collins, L. Shayesteh, N. Doggett, K. R. Johnson, M. J. Wheelock, J. Herman, S. Baylin, D. Pinkel, and J. Gray (1998). Mechanisms of inactivation of E-cadherin in breast cancer cell lines. Cancer Res. 58:1972-1977.PubMedGoogle Scholar
  39. 39.
    G. Hennig, J. Behrens, M. Truss, S. Frisch, E. Reichmann, and W. Birchmeier (1995). Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. Oncogene 11:475-484.PubMedGoogle Scholar
  40. 40.
    G. Mbalaviele, C. R. Dunstan, A. Sasaki, P. J. Williams, G. R. Mundy, and T. Yoneda (1996). E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastases in an experimental metastasis model. Cancer Res. 56:4063-4070.PubMedGoogle Scholar
  41. 41.
    S. Meiners, V. Brinkmann, H. Naundorf, and W. Birchmeier (1998). Role of morphogenetic factors in metastasis of mammary carcinoma cells. Oncogene 16:9-20.PubMedGoogle Scholar
  42. 42.
    M. E. Bracke, C. Charlier, E. A. Bruyneel, C. Labit, M. M. Mareel, and V. Castronovo (1994). Tamoxifen restores the E-cadherin function in human breast cancer MCF-7/6 cells and suppresses their invasive phenotype. Cancer Res. 54:4607-4609.PubMedGoogle Scholar
  43. 43.
    S. Z. Yang, N. Kohno, K. Kondo, A. Yokoyama, H. Hamada, K. Hiwada, and M. Miyake (1999). Adriamycin activates Ecadherin-mediated cell-cell adhesion in human breast cancer cells. Int. J. Oncol. 15:1109-1115.PubMedGoogle Scholar
  44. 44.
    M. E. Bracke, B. M. Vyncke, E. A. Bruyneel, S. J. Vermeulen, G. K. De Bruyne, N. A. Van Larebeke, K. Vleminckx, F. M. Van Roy, and M. M. Mareel (1993). Insulin-like growth factor I activates the invasion suppressor function of E-cadherin in MCF-7 human mammary carcinoma cells in vitro. Br. J. Cancer. 68:282-289.PubMedGoogle Scholar
  45. 45.
    Q. Meng, B. Gao, I. D. Goldberg, E. M. Rosen, and S. Fan (2000). Stimulation of cell invasion and migration by alcohol in breast cancer cells. Biochem. Biophys. Res. Commun. 273:448-453.PubMedGoogle Scholar
  46. 46.
    R. Moll, M. Mitze, U. H. Frixen, and W. Birchmeier (1993). Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. Am. J. Pathol. 143:1731-1742.PubMedGoogle Scholar
  47. 47.
    C. Gamallo, J. Palacios, A. Suarez, A. Pizarro, P. Navarro, M. Quintanilla, and A. Cano (1993). Correlation of E-cadherin expression with differentiation grade and histological type in breast carcinoma. Am. J. Pathol. 142:987-993.PubMedGoogle Scholar
  48. 48.
    S. A. Rasbridge, C. E. Gillett, S. A. Sampson, F. S. Walsh, and R. R. Millis (1993). Epithelial (E-) and Placental (P-) cadherin cell adhesion molecule expression in breast carcinoma. J. Pathol. 169:245-250.PubMedGoogle Scholar
  49. 49.
    S. M. Siitonen, J. T. Kononen, H. J. Helin, I. S. Rantala, K. A. Holli, and J. J. Isola (1996). Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am. J. Clin. Pathol. 105:394-402.PubMedGoogle Scholar
  50. 50.
    W. J. De Leeuw, G. Berx, C. B. Vos, J. L. Peterse, M. J. Van de Vijver, S. Litvinov, F. Van Roy, C. J. Cornelisse, and A. M. Cleton-Jansen (1997). Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J. Pathol. 183:404-411.PubMedGoogle Scholar
  51. 51.
    C. B. Vos, A. M. Cleton-Jansen, G. Berx, W. J. de Leeuw, N. T. ter Haar, F. van Roy, C. J. Cornelisse, J. L. Peterse, and M. J. van de Vijver (1997). E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br. J. Cancer 76:1131-1133.PubMedGoogle Scholar
  52. 52.
    G. Keller, H. Vogelsang, I. Becker, J. Hutter, K. Ott, S. Candidus, T. Grundei, K. F. Becker, J. Mueller, J. R. Siewert, and H. Hofler (1999). Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am. J. Pathol. 155:337-342.PubMedGoogle Scholar
  53. 53.
    R. Hashizume, H. Koizumi, A. Ihara, T. Ohta, and T. Uchikoshi (1996). Expression of β-catenin in normal breast tissue and breast carcinoma: A comparative study with epithelial cadherin and β-catenin. Histopathology 29:139-146.PubMedGoogle Scholar
  54. 54.
    A. Peralta Soler, K. A. Knudsen, H. Salazar, A. C. Han, and A. A. Keshgegian (1999). P-cadherin expression in breast carcinoma indicates poor survival. Cancer 86:1263-1272.PubMedGoogle Scholar
  55. 55.
    H. Oka, H. Shiozaki, K. Kobayashi, M. Inoue, H. Tahara, T. Kobayashi, Y. Takatsuka, N. Matsuyoshi, S. Hirano, M. Takeichi, and T. Mori (1993). Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res. 53:1696-1701.PubMedGoogle Scholar
  56. 56.
    S. K. Gupta, A. G. Douglas-Jones, B. Jasani, J. M. Morgan, M. Pignatelli, and R. E. Mansel (1997). E-cadherin (E-cad) expression in duct carcinoma in situ (DCIS) of the breast. Virchows Arch. 430:23-28.PubMedGoogle Scholar
  57. 57.
    C. Charpin, S. Garcia, C. Bouvier, B. Devictor, L. Andrac, R. Choux, and M. Lavaut (1997). E-cadherin quantitative immunocytochemical assays in breast carcinomas. J. Pathol. 181:294-300.PubMedGoogle Scholar
  58. 58.
    W. Zschiesche, I. Schonborn, J. Behrens, K. Herrenknecht, F. Hartveit, P. Lilleng, and W. Birchmeier (1997). Expression of E-cadherin and catenins in invasive mammary carcinomas. Anticancer Res. 17:561-567.PubMedGoogle Scholar
  59. 59.
    J. L. Jones, J. E. Royall, and R. A. Walker (1996). E-cadherin relates to EGFR expression and lymph node metastasis in primary breast carcinoma. Br. J. Cancer. 74:1237-1241.PubMedGoogle Scholar
  60. 60.
    I. K. Bukholm, J. M. Nesland, and A. L. Borresen-Dale (2000). Re-expression of E-cadherin, α-catenin, and β-catenin, but not of γ-catenin, in tissue from breast cancer patients. J. Pathol. 190:15-19.PubMedGoogle Scholar
  61. 61.
    I. Funke, S. Fries, M. Rolle, M. M. Heiss, M. Untch, H. Bohmert, F. W. Schildberg, and K. W. Jauch (1996). Comparative analysis of bone marrow micrometastases in breast and gastric cancer. Int. J. Cancer. 65:755-761.PubMedGoogle Scholar
  62. 62.
    G. P. Cowley and M. E. Smith (1995). Modulation of E-cadherin expression and morphological phenotype in the intravascular component of adenocarcinomas. Int. J. Cancer 60:325-329.PubMedGoogle Scholar
  63. 63.
    J. R. Graff, E. Gabrielson, H. Fujii, S. B. Baylin, and J. G. Herman (2000). Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J. Biol. Chem. 275:2727-2732.PubMedGoogle Scholar
  64. 64.
    C. Charpin, S. Garcia, P. Bonnier, F. Martini, L. Andrac, R. Choux, M. N. Lavaut, and C. Allasia (1998). Reduced Ecadherin immunohistochemical expression in node-negative breast carcinomas correlates with 10-year survival. Am. J. Clin. Pathol. 109:431-438.PubMedGoogle Scholar
  65. 65.
    T. M. Maguire, S. G. Shering, E. W. McDermott, N. O'Higgins, J. J. Fennelly, J. Crown, and M. J. Duffy (1997). Assay of E-cadherin by ELISA in human breast cancers. Eur. J. Cancer 33:404-408.PubMedGoogle Scholar
  66. 66.
    R. Heimann, F. Lan, R. McBride, and S. Hellman (2000). Separating favorable from unfavorable prognostic markers in breast cancer: The role of E-cadherin. Cancer Res. 60:298-304.PubMedGoogle Scholar
  67. 67.
    K. S. Asgeirsson, J. G. Jonasson, L. Tryggvadottir, K. Olafsdottir, J. R. Sigurgeirsdottir, S. Invarsson, and H. M. Ogmundsdottir (2000). Altered expression of E-cadherin in breast cancer: Patterns, mechanisms and clinical significance. Eur. J. Cancer. 36:1098-1106.PubMedGoogle Scholar
  68. 68.
    P. Lipponen, E. Saarelainen, S. Aaltomaa, and K. Syrjanen (1994). Expression of E-cadherin (E-CD) as related to other prognostic factors and survival in breast cancer. J. Pathol. 174:101-109.PubMedGoogle Scholar
  69. 69.
    M. A. Gonzalez, S. E. Pinder, P. M. Wencyk, J. A. Bell, C. W. Elston, R. I. Nicholson, J. F. Robertson, R. W. Blamey, and I. O. Ellis (1999). An immunohistochemical examination of the expression of E-cadherin, α-and β/γ-catenins, and α2-and β1-integrins in invasive breast cancer. J. Pathol. 187:523-529.PubMedGoogle Scholar
  70. 70.
    D. S. Tan, H. W. Potts, A. C. Leong, D. Skilton, W. H. Harris, R. D. Liebmann, and A. M. Hanby (1999). The biological and prognostic significance of cell polarity and E-cadherin in grade I infiltrating ductal carcinoma of the breast. J. Pathol. 189:20-27.PubMedGoogle Scholar
  71. 71.
    D. L. Rimm, J. H. Sinard, and J. S. Morrow (1995). Reduced alpha-catenin and E-cadherin expression in breast cancer. Lab Invest. 72:506-512.PubMedGoogle Scholar
  72. 72.
    I. K. Bukholm, J. M. Nesland, R. Karesen, U. Jacobsen, and A. L. Borresen-Dale (1998). E-cadherin and α-, β-, and γ-catenin protein expression in relation to metastasis in human breast carcinoma. J. Pathol. 185:262-266.PubMedGoogle Scholar
  73. 73.
    J. M. Williams and C. W. Daniel (1983). Mammary ductal elongation: Differentiation of myoepithelium and basal lamina during branching morphogenesis. Devlop. Biol. 97:274-290.Google Scholar
  74. 74.
    J. Palacios, N. Benito, A. Pizarro, A. Suarez, J. Espada, A. Cano, and C. Gamallo (1995). Anomalous expression of P-cadherin in breast carcinoma. Correlation with E-cadherin expression and pathological features. Am. J. Pathol. 146:605-612.PubMedGoogle Scholar
  75. 75.
    G. Kremmidiotis, E. Baker, J. Crawford, H. J. Eyre, J. Nahmias, and D. F. Callen (1998). Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity. Genomics 49:467-471.PubMedGoogle Scholar
  76. 76.
    S. W. Lee (1996). H-cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer. Nat. Med. 2:776-782.PubMedGoogle Scholar
  77. 77.
    S. W. Lee, C. L. Reimer, D. B. Campbell, P. Cheresh, R. B. Duda, and O. Kocher (1998). H-cadherin expression inhibits in vitro invasiveness and tumor formation in vivo. Carcinogenesis 19:1157-1159.PubMedGoogle Scholar
  78. 78.
    C. L. Sommers, E. P. Gelmann, R. Kemler, P. Cowin, and S. W. Byers (1994). Alterations in β-catenin phosphorylation and plakoglobin expression in human breast cancer cells. Cancer Res. 54:3544-3552.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Margaret J. Wheelock
    • 1
  • Alejandro Peralta Soler
    • 2
  • Karen A. Knudsen
    • 2
  1. 1.Department of BiologyUniversity of ToledoToledo
  2. 2.Lankenau Institute for Medical ResearchWynnewood

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