Skip to main content
SpringerLink
Log in

The Role of Connexin-Mediated Cell–Cell Communication in Breast Cancer Metastasis

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Gap junctional intercellular communication (GJIC) is a form of cell–cell communication mediating the exchange of small molecules between neighboring cells. Gap junctions (GJs) are formed by connexins (Cxs), and are subject to tight and dynamic regulation. They are involved in the cell cycle, differentiation, and cell signaling. The loss of Cxs and GJs is a hallmark of carcinogenesis, while their induction in cancer cells leads to a reversal of the cancer phenotype, induction of differentiation, and regulation of cell growth. On the basis of the observations about Cx loss in breast cancer, this review examines Cxs' involvement in breast cancer metastasis. Previous work indicates that Cx expression is inversely correlated to metastatic potential. This is probably because of the loss of cooperation between neighboring cells, leading to cell heterogeneity and cell dissociation in the tumor. The possible involvement of Cx activity during metastasis will be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. J.W. Holder, E. Elmore, and J. C. Barrett (1993). Gap junction function and cancer. Cancer Res. 53:3475-3485.

    Google Scholar 

  2. J. E. Trosko and R. J. Ruch (1998). Cell-cell communication in carcinogenesis. Front Biosci. 3:D208-D236. (Process Citation)

    Google Scholar 

  3. D. A. Goodenough, J. A. Goliger, and D. L. Paul (1996). Connexins, connexons, and intercellular communication. Annu. Rev. Biochem. 65:475-502.

    Google Scholar 

  4. M. Zhang and S. S. Thorgeirsson (1994). Modulation of connexins during differentiation of oval cells into hepatocytes. Exp. Cell Res. 213:37-42.

    Google Scholar 

  5. P. Monaghan and D. Moss (1996). Connexin expression and gap junctions in the mammary gland. Cell Biol. Int. 20:121-125.

    Google Scholar 

  6. A. Pozzi, B. Risek, D. T. Kiang, N. B. Gilula, and N. M. Kumar (1995). Analysis of multiple gap junction gene products in the rodent and human mammary gland. Exp. Cell Res. 220:212-219.

    Google Scholar 

  7. S. Jamieson, J. J. Going, R. D'Arcy, and W. D. George (1998). Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours. J. Pathol. 184:37-43.

    Google Scholar 

  8. D. Locke (1998). Gap junctions in normal and neoplastic mammary gland. J. Pathol. 186:343-349.

    Google Scholar 

  9. P. Monaghan, C. Clarke, N. P. Perusinghe, D. W. Moss, X. Y. Chen, and W. H. Evans (1996). Gap junction distribution and connexin expression in human breast. Exp. Cell Res. 223:29-38.

    Google Scholar 

  10. E. C. Beyer, D. L. Paul, and D. A. Goodenough (1987). Connexin43: Aprotein from rat heart homologous to a gap junction protein from liver. J. Cell Biol. 105:2621-2629.

    Google Scholar 

  11. A. G. Reaume, P. A. de Sousa, S. Kulkarni, B. L. Langille, D. Zhu, T. C. Davies, S. C. Juneja, G. M. Kidder, and J. Rossant (1995). Cardiac malformation in neonatal mice lacking connexin43. Science 267:1831-1834. (comments)

    Google Scholar 

  12. G. I. Fishman, R. L. Eddy, T. B. Shows, L. Rosenthal, and L. A. Leinwand (1991). The human connexin gene family of gap junction proteins: Distinct chromosomal locations but similar structures. Genomics 10:250-256.

    Google Scholar 

  13. T. Toyofuku, M. Yabuki, K. Otsu, T. Kuzuya, M. Hori, and M. Tada (1998). Direct association of the gap junction protein connexin-43 with ZO-1 in cardiac myocytes. J. Biol. Chem. 273:12725-12731.

    Google Scholar 

  14. H. Yamasaki, M. Mesnil, Y. Omori, N. Mironov, and V. Krutovskikh (1995). Intercellular communication and carcinogenesis. Mutat. Res. 333:181-188.

    Google Scholar 

  15. M. M. Atkinson, P. D. Lampe, H. H. Lin, R. Kollander, X. R. Li, and D.T. Kiang (1995). CyclicAMPmodifies the cellular distribution of connexin43 and induces a persistent increase in the junctional permeability of mouse mammary tumor cells. J. Cell Sci. 108:3079-3090.

    Google Scholar 

  16. H. Guo, P. Acevedo, F.D. Parsa, and J. S. Bertram (1992). Gapjunctional protein connexin 43 is expressed in dermis and epidermis of human skin: Differential modulation by retinoids. J. Invest. Dermatol. 99:460-467.

    Google Scholar 

  17. J. S. Bertram (1999). Carotenoids and gene regulation. Nutr. Rev. 57:182-191.

    Google Scholar 

  18. Y. S. Jou, B. Layhe, D. F. Matesic, C. C. Chang, A. W. de Feijter, L. Lockwood, C. W. Welsch, J. E. Klaunig, and J. E. Trosko (1995). Inhibition of gap junctional intercellular communication and malignant transformation of rat liver epithelial cells by neu oncogene. Carcinogenesis 16:311-317.

    Google Scholar 

  19. A. Hofer, J. C. Saez, C. C. Chang, J. E. Trosko, D. C. Spray, and R. Dermietzel (1996). C-erbB2/neu transfection induces gap junctional communication incompetence in glial cells. J. Neurosci. 16:4311-4321.

    Google Scholar 

  20. M.Y. Kanemitsu, L.W. Loo, S. Simon, A.F. Lau, and W. Eckhart (1997). Tyrosine phosphorylation of connexin 43 by v-Src is mediated by SH2 and SH3 domain interactions. J. Biol. Chem. 272:22824-22831.

    Google Scholar 

  21. L. W. Loo, J. M. Berestecky, M. Y. Kanemitsu, and A. F. Lau (1995). pp60src-mediated phosphorylation of connexin 43, a gap junction protein. J. Biol. Chem. 270:12751-12761.

    Google Scholar 

  22. A.W. de Feijter, D. F. Matesic, R. J. Ruch, X. Guan, C.C. Chang, and J. E. Trosko (1996). Localization and function of the connexin 43 gap-junction protein in normal and various oncogeneexpressing rat liver epithelial cells. Mol. Carcin. 16:203-212.

    Google Scholar 

  23. D. W. Laird, P. Fistouris, G. Batist, L. Alpert, H. T. Huynh, G. D. Carystinos, and M.A. Alaoui-Jamali (1999). Deficiency of connexin43 gap junctions is an independent marker for breast tumors. Cancer Res. 59:4104-4110.

    Google Scholar 

  24. L. S. Musil, B. A. Cunningham, G. M. Edelman, and D. A. Goodenough (1990). Differential phosphorylation of the gap junction protein connexin43 in junctional communicationcompetent and-deficient cell lines. J. Cell Biol. 111:2077-2088.

    Google Scholar 

  25. W. M. Jongen, D. J. Fitzgerald, M. Asamoto, C. Piccoli, T. J. Slaga, D. Gros, M. Takeichi, and H. Yamasaki (1991). Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin. J. Cell Biol. 114:545-555.

    Google Scholar 

  26. R. A. Meyer, D.W. Laird, J. P. Revel, and R.G. Johnson (1992). Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies. J. Cell Biol. 119:179-189.

    Google Scholar 

  27. M. Hsu, T. Andl, G. Li, J. L. Meinkoth, and M. Herlyn (2000). Cadherin repertoire determines partner-specific gap junctional communication during melanoma progression. J. Cell Sci. 113:1535-1542.

    Google Scholar 

  28. M. A. van der Heyden, M.B. Rook, M. M. Hermans, G. Rijksen, J. Boonstra, L. H. Defize, and O. H. Destree (1998). Identification of connexin43 as a functional target for Wnt signalling. J. Cell Sci. 111:1741-1749.

    Google Scholar 

  29. L. Koffler, S. Roshong, P. Kyu, I. K. Cesen-Cummings, D. C. Thompson, L. D. Dwyer-Nield, P. Rice, C. Mamay, A. M. Malkinson, and R. J. Ruch (2000). Growth inhibition in G(1) and altered expression of cyclin D1 and p27(kip-1) after forced connexin expression in lung and liver carcinoma cells. J. Cell Biochem. 79:347-354. (Process Citation)

    Google Scholar 

  30. S. C. Chen, D. B. Pelletier, P. Ao, and A. L. Boynton (1995). Connexin43 reverses the phenotype of transformed cells and alters their expression of cyclin/cyclin-dependent kinases. Cell Growth Differ. 6:681-690.

    Google Scholar 

  31. D. B. Gros and H. J. Jongsma (1996). Connexins in mammalian heart function. Bioessays 18:719-730.

    Google Scholar 

  32. R. Dermietzel and D. C. Spray (1993). Gap junctions in the brain:Where, what type, how many and why? Trends Neurosci. 16:186-192.

    Google Scholar 

  33. H. J. Donahue, Z. Li, Z. Zhou, and C. E. Yellowley (2000). Differentiation of human fetal osteoblastic cells and gap junctional intercellular communication. Am. J. Physiol Cell Physiol 278:C315-C322.

    Google Scholar 

  34. W. R. Lowenstein and Y. Kanno (1966). Intercellular communication and the control of tissue growth: Lack of communication between cancer cells. Nature 209:1248-1249.

    Google Scholar 

  35. I. S. Fentiman (1980). Cell communication in breast cancer. Ann. R. Coll. Surg. Engl. 62:280-286.

    Google Scholar 

  36. W. R. Loewenstein (1979). Junctional intercellular communication and the control of growth. Biochim. Biophys. Acta 560:1-65.

    Google Scholar 

  37. V. Krutovskikh, G. Mazzoleni, N. Mironov, Y. Omori, A. M. Aguelon, M. Mesnil, F. Berger, C. Partensky, and H. Yamasaki (1994). Altered homologous and heterologous gapjunctional intercellular communication in primary human liver tumors associated with aberrant protein localization but not gene mutation of connexin 32. Int. J. Cancer 56:87-94.

    Google Scholar 

  38. I. V. Budunova and G. M. Williams (1994). Cell culture assays for chemicals with tumor-promoting or tumor-inhibiting activity based on the modulation of intercellular communication. Cell Biol. Toxicol. 10:71-116.

    Google Scholar 

  39. H. S. Rosenkranz, N. Pollack, and A. R. Cunningham (2000). Exploring the relationship between the inhibition of gap junctional intercellular communication and other biological phenomena. Carcinogenesis 21:1007-1011.

    Google Scholar 

  40. M. Rosenkranz, H. S. Rosenkranz, and G. Klopman (1997). Intercellular communication, tumor promotion and nongenotoxic carcinogenesis: Relationships based upon structural considerations. Mutat. Res. 381:171-188.

    Google Scholar 

  41. V. A. Krutovskikh, M. Oyamada, and H. Yamasaki (1991). Sequential changes of gap-junctional intercellular communications during multistage rat liver carcinogenesis: Direct measurement of communication in vivo. Carcinogenesis 12:1701-1706.

    Google Scholar 

  42. H. Yamasaki (1990). Gap junctional intercellular communication and carcinogenesis. Carcinogenesis 11:1051-1058.

    Google Scholar 

  43. S. A. Garber, M. J. Fernstrom, G. D. Stoner, and R. J. Ruch (1997). Altered gap junctional intercellular communication in neoplastic rat esophageal epithelial cells. Carcinogenesis 18:1149-1153.

    Google Scholar 

  44. C. Tomasetto, M. J. Neveu, J. Daley, P. K. Horan, and R. Sager (1993). Specificity of gap junction communication among human mammary cells and connexin transfectants in culture. J. Cell Biol. 122:157-167.

    Google Scholar 

  45. S. W. Lee, C. Tomasetto, D. Paul, K. Keyomarsi, and R. Sager (1992). Transcriptional downregulation of gap-junction proteins blocks junctional communication in human mammary tumor cell lines. J. Cell Biol. 118:1213-1221.

    Google Scholar 

  46. K. K. Hirschi, C. E. Xu, T. Tsukamoto, and R. Sager (1996). Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential. Cell Growth Differ. 7:861-870.

    Google Scholar 

  47. K. K. Wilgenbus, C. J. Kirkpatrick, R. Knuechel, K. Willecke, and O. Traub (1992). Expression of Cx26, Cx32 and Cx43 gap junction proteins in normal and neoplastic human tissues. Int. J. Cancer 51:522-529.

    Google Scholar 

  48. G. P. Robertson, A. B. Coleman, and T.G. Lugo (1996). Mechanisms of human melanoma cell growth and tumor suppression by chromosome 6. Cancer Res. 56:1635-1641.

    Google Scholar 

  49. M. P. Piechocki, R. D. Burk, and R. J. Ruch (1999). Regulation of connexin32 and connexin43 gene expression by DNA methylation in rat liver cells. Carcinogenesis 20:401-406.

    Google Scholar 

  50. L. S. Musil, A. C. Le, J. K. VanSlyke, and L. M. Roberts (2000). Regulation of connexin degradation as a mechanism to increase gap junction assembly and function. J. Biol. Chem. 275:25207-25215.

    Google Scholar 

  51. B. Rose, P. P. Mehta, and W. R. Loewenstein (1993). Gapjunction protein gene suppresses tumorigenicity. Carcinogenesis 14:1073-1075.

    Google Scholar 

  52. T. J. King, L. H. Fukushima, T. A. Donlon, A. D. Hieber, K. A. Shimabukuro, and J. S. Bertram (2000). Correlation between growth control, neoplastic potential and endogenous connexin43 expression in HeLa cell lines: Implications for tumor progression. Carcinogenesis 21:311-315.

    Google Scholar 

  53. D. Zhu, G. M. Kidder, S. Caveney, and C. C. Naus (1992). Growth retardation in glioma cells cocultured with cells overexpressing a gap junction protein. Proc. Natl. Acad. Sci. U.S.A. 89:10218-10221.

    Google Scholar 

  54. R. P. Huang, Y. Fan, M. Z. Hossain, A. Peng, Z. L. Zeng, and A. L. Boynton (1998). Reversion of the neoplastic phenotype of human glioblastoma cells by connexin 43 (cx43). Cancer Res. 58:5089-5096.

    Google Scholar 

  55. V. A. Krutovskikh, S. M. Troyanovsky, C. Piccoli, H. Tsuda, M. Asamoto, and H. Yamasaki (2000). Differential effect of subcellular localization of communication impairing gap junction protein connexin43 on tumor cell growth in vivo. Oncogene 19:505-513.

    Google Scholar 

  56. D. L. Dankort and W. J. Muller (2000). Signal transduction in mammary tumorigenesis: A transgenic perspective. Oncogene 19:1038-1044.

    Google Scholar 

  57. R. Heimann and S. Hellman (2000). Individual characterisation of the metastatic capacity of human breast carcinoma. Eur. J. Cancer 36:1631-1639.

    Google Scholar 

  58. J. Yokota (2000). Tumor progression and metastasis. Carcinogenesis 21:497-503.

    Google Scholar 

  59. J. Russo and I. H. Russo (2001). The pathway of neoplastic transformation of human breast epithelial cells. Radiat. Res. 155:151-154.

    Google Scholar 

  60. R. Engers and H. E. Gabbert (2000). Mechanisms of tumor metastasis: Cell biological aspects and clinical implications. J. Cancer Res. Clin. Oncol. 126:682-692.

    Google Scholar 

  61. M. J. Seraj, R. S. Samant, M. F. Verderame, and D. R. Welch (2000). Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res. 60:2764-2769.

    Google Scholar 

  62. A. Navolotski, A. Rumjnzev, H. Lu, D. Proft, P. Bartholmes, and K. S. Zanker (1997). Migration and gap junctional intercellular communication determine the metastatic phenotype of human tumor cell lines. Cancer Lett. 118:181-187.

    Google Scholar 

  63. G. L. Nicolson, K. M. Dulski, and J. E. Trosko (1988). Loss of intercellular junctional communication correlates with metastatic potential in mammary adenocarcinoma cells. Proc. Natl. Acad. Sci. U.S.A. 85:473-476.

    Google Scholar 

  64. J. Hamada, N. Takeichi, and H. Kobayashi (1988). Metastatic capacity and intercellular communication between normal cells and metastatic cell clones derived from a rat mammary carcinoma. Cancer Res. 48:5129-5132.

    Google Scholar 

  65. J. Hamada, N. Takeichi, J. Ren, and H. Kobayashi (1991). Junctional communication of highly and weakly metastatic variant clones from a rat mammary carcinoma in primary and metastatic sites. Invasion Metastasis 11:149-157.

    Google Scholar 

  66. J. Ren, J. Hamada, N. Takeichi, S. Fujikawa, and H. Kobayashi (1990). Ultrastructural differences in junctional intercellular communication between highly and weakly metastatic clones derived from rat mammary carcinoma. Cancer Res. 50:358-362.

    Google Scholar 

  67. M. M. Saunders, M. J. Seraj, Z. Li, Z. Zhou, C. R. Winter, D. R. Welch, and H. J. Donahue (2001). Breast cancer metastatic potential correlates with a breakdown in homospecific and heterospecific gap junctional intercellular communication. Cancer Res. 61:1765-1767.

    Google Scholar 

  68. A. Shoji, Y. Sakamoto, T. Tsuchiya, K. Moriyama, T. Kaneko, T. Okubo, M. Umeda, and K. Miyazaki (1997). Inhibition of tumor promoter activity toward mouse fibroblasts and their in vitro transformation by tissue inhibitor of metalloproteinases-1 (TIMP-1). Carcinogenesis 18:2093-2100.

    Google Scholar 

  69. W. H. Fletcher, W. W. Shiu, T. A. Ishida, D. L. Haviland, and C. F. Ware (1987). Resistance to the cytolytic action of lymphotoxin and tumor necrosis factor coincides with the presence of gap junctions uniting target cells. J. Immunol. 139:956-962.

    Google Scholar 

  70. M. E. el Sabban and B. U. Pauli (1994). Adhesion-mediated gap junctional communication between lung-metastatatic cancer cells and endothelium. Invasion Metastasis 14:164-176.

    Google Scholar 

  71. A. Ito, F. Katoh, T. R. Kataoka, M. Okada, N. Tsubota, H. Asada, K. Yoshikawa, S. Maeda, Y. Kitamura, H. Yamasaki, and H. Nojima (2000). A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J. Clin. Invest. 105:1189-1197.

    Google Scholar 

  72. Y. Kamibayashi, Y. Oyamada, M. Mori, and M. Oyamada (1995). Aberrant expression of gap junction proteins (connexins) is associated with tumor progression during multistage mouse skin carcinogenesis in vivo. Carcinogenesis 16:1287-1297.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Oncology and Pharmacology & Therapeutics, McGill University Centre for Translational Research in Cancer, Sir Mortimer B. Davis – Jewish General Hospital, Montreal, Canada

    George D. Carystinos, Andrew Bier & Gerald Batist

Authors
  1. George D. Carystinos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew Bier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerald Batist
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carystinos, G.D., Bier, A. & Batist, G. The Role of Connexin-Mediated Cell–Cell Communication in Breast Cancer Metastasis. J Mammary Gland Biol Neoplasia 6, 431–440 (2001). https://doi.org/10.1023/A:1014787014851

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1014787014851

Search

Navigation