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Integrin Laminin Receptors and Breast Carcinoma Progression

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Abstract

This review explores the mechanistic basis of breast carcinoma progression by focusing on the contribution of integrins. Integrins are essential for progression not only for their ability to mediate physical interactions with extracellular matrices but also for their ability to regulate signaling pathways that control actin dynamics and cell movement, as well as for growth and survival. Our comments center on the α6 integrins (α6β1 and α6β4), which are receptors for the laminin family of basement membrane components. Numerous studies have implicated these integrins in breast cancer progression and have provided a rationale for studying the mechanistic basis of their contribution to aggressive disease. Recent work by our group and others on mechanisms of breast carcinoma invasion and survival that are influenced by the α6 integrins are discussed.

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REFERENCES

  1. E. R. Fearon (1999). Cancer progression. Curr. Biol. 9:R873-875.

    PubMed  Google Scholar 

  2. D. Hanahan and R. A. Weinberg (2000). The hallmarks of cancer. Cell 100:57-70.

    Article  PubMed  Google Scholar 

  3. E. Rodriguez-Boulan and W. J. Nelson (1989). Morphogenesis of the polarized epithelial cell phenotype. Science 245:718-725.

    Google Scholar 

  4. H. Colognato and P. Yurchenco (2000). Form and function: The laminin family of heterotrimers. Developmental Dynamics 218:213-234.

    PubMed  Google Scholar 

  5. N. Boudreau and M. J. Bissell (1998). Extracellular matrix signaling: Integration of form and function in normal and malignant cells. Curr. Opin. Cell. Biol. 10:640-646.

    PubMed  Google Scholar 

  6. M. J. Bissell, V. M. Weaver, S. A. Lelievre, F. Wang, O. W. Petersen, and K. L. Schmeichel (1999). Tissue structure, nuclear organization, and gene expression in normal and malignant breast. Cancer Res. 59:1757-1763s.

    PubMed  Google Scholar 

  7. R. S. Cotran, V. Kumar, and T. Collins (1999). Robbins Pathological Basis of Disease. Saunders, Philadelphia.

    Google Scholar 

  8. T. Tani, A. Lumme, A. Linnala, E. Kivilaakso, T. Kiviluoto, R. E. Burgeson, L. Kangas, I. Leivo, and I. Virtanen (1997). Pancreatic carcinomas deposit laminin-5, preferably adhere to laminin-5, and migrate on the newly deposited basement membrane. Am. J. Pathol. 151:1289-1302.

    PubMed  Google Scholar 

  9. H. Mizushima, H., Y. Miyagi, Y. Kikkawa, N. Yamanaka, H. Yasumitsu, K. Misugi, and K. Miyazaki (1996). Differential expression of laminin-5/ladsin subunits in human tissues and cancer cell lines and their induction by tumor promoter and growth factors. J. Biochem. (Tokyo). 120:1196-1202.

    PubMed  Google Scholar 

  10. L. M. Shaw, I. Rabinovitz, H. H. Wang, A. Toker, and A. M. Mercurio (1997). Activation of phosphoinositide 3-OH kinase by the α6β4 integrin promotes carcinoma invasion. Cell 91:949-960.

    PubMed  Google Scholar 

  11. R. E. Bachelder, M. J. Ribick, A. Marchetti, R. Falcioni, S. Soddu, K. R. Davis, and A. M. Mercurio (1999). p53 inhibits α6β4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKt/PKB. J. Cell. Biol. 147:1063-1072.

    PubMed  Google Scholar 

  12. G. E. Plopper, S. Z. Domanico, V. Cirulli, W. B. Kiosses, and V. Quaranta (1998). Migration of breast epithelial cells on Laminin-5: Differential role of integrins in normal and transformed cell types. Breast Cancer Res. Treat. 51:57-69.

    PubMed  Google Scholar 

  13. N. Koshikawa, G. Giannelli, V. Cirulli, K. Miyazaki, and V. Quaranta (2000). Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J. Cell. Biol. 148:615-624.

    PubMed  Google Scholar 

  14. A. Mercurio (1995). Receptors for the laminins. Achieving specificity through cooperation. Trends in Cell biology 5:419-423.

    PubMed  Google Scholar 

  15. L. M. Shaw (1999). Integrin function in breast carcinoma progression. J. Mammary Gland. Biol. Neoplasia 4:367-376.

    PubMed  Google Scholar 

  16. K. Friedrichs, P. Ruiz, F. Franke, I. Gille, H. J. Terpe, and B. A. Imhof (1995). High expression level of α6 integrin in human breast carcinoma is correlated with reduced survival. Cancer Res. 55:901-906.

    PubMed  Google Scholar 

  17. E. Tagliabue, C. Ghirelli, P. Squicciarini, P. Aiello, M. I. Colnaghi, and S. Menard (1998). Prognostic value of α6β4 integrin expression in breast carcinomas is affected by laminin production from tumor cells. Clin. Cancer Res. 4:407-410.

    PubMed  Google Scholar 

  18. U. M. Wewer, L. M. Shaw, R. Albrechtsen, and A. M. Mercurio (1997). The integrin α6β1 promotes the survival of metastatic human breast carcinoma cells in mice. Am. J. Pathol. 151:1191-1198.

    PubMed  Google Scholar 

  19. R. Mukhopadhyay, R. L. Theriault, and J. E. Price (1999). Increased levels of α6 integrins are associated with the metastatic phenotype of human breast cancer cells. Clin. Exp. Metastasis 17:325-332.

    PubMed  Google Scholar 

  20. W. G. Stetler-Stevenson, S. Aznavoorian, and L. A. Liotta (1993). Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu. Rev. Cell. Biol. 9:541-573.

    PubMed  Google Scholar 

  21. E. D. Hay (1995). Anoverview of epithelio-mesenchymal transformation. Acta. Anat. (Basel) 154:8-20.

    Google Scholar 

  22. J. P. Thiery and D. Chopin (1999). Epithelial cell plasticity in development and tumor progression. Cancer Metastasis Rev. 18:31-42.

    PubMed  Google Scholar 

  23. C. Birchmeier, W. Birchmeier, and B. Brand-Saberi (1996). Epithelial-mesenchymal transitions in cancer progression. Acta Anat. (Basel) 156:217-226.

    Google Scholar 

  24. B. P. Wijnhoven, W. N. Dinjens, and M. Pignatelli (2000). E-cadherin-catenin cell-cell adhesion complex and human cancer. Br. J. Surg. 87:992-1005.

    PubMed  Google Scholar 

  25. J. Behrens (1999). Cadherins and catenins: Role in signal transduction and tumor progression. Cancer Metastasis Rev. 18:15-30.

    PubMed  Google Scholar 

  26. W. Birchmeier, J. Hulsken, and J. Behrens (1995). E-cadherin as an invasion suppressor. Ciba Found Symp. 189:124-136.

    PubMed  Google Scholar 

  27. W. Birchmeier (1995). E-cadherin as a tumor (invasion) suppressor gene. Bioessays 17:97-99.

    PubMed  Google Scholar 

  28. M. G. Nievers, R. Q. Schaapveld, and A. Sonnenberg (1999). Biology and function of hemidesmosomes. Matrix Biol. 18:5-17.

    PubMed  Google Scholar 

  29. L. M. Bergstraesser, G. Srinivasan, J. C. Jones, S. Stahl, and S. A. Weitzman (1995). Expression of hemidesmosomes and component proteins is lost by invasive breast cancer cells. Am. J. Pathol. 147:1823-1839.

    PubMed  Google Scholar 

  30. I. Rabinovitz and A. M. Mercurio (1996). The integrin α6β4 and the biology of carcinoma. Biochem. Cell. Biol. 74:811-821.

    PubMed  Google Scholar 

  31. C. Chao, M. M. Lotz, A. C. Clarke, and A. M. Mercurio (1996). A function for the integrin α6β4 in the invasive properties of colorectal carcinoma cells. Cancer Res. 56:4811-4819.

    PubMed  Google Scholar 

  32. H. Sun, S. A. Santoro, and M. M. Zutter (1998). Downstream events in mammary gland morphogenesis mediated by reexpression of the α2β1 integrin: The role of the α6 and β4 integrin subunits. Cancer Res. 58:2224-2233.

    PubMed  Google Scholar 

  33. K. L. O'Connor, L. M. Shaw, and A. M. Mercurio (1998). Release of cAMP gating by the α6β4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells. J. Cell. Biol. 143:1749-1760.

    PubMed  Google Scholar 

  34. L. Bonaccorsi, V. Carloni, M. Muratori, A. Salvadori, A. Giannini, M. Carini, M. Serio, G. Forti, and E. Baldi (2000). Androgen receptor expression in prostate carcinoma cells suppresses α6β4 integrin-mediated invasive phenotype. Endocrinology 141:3172-3182.

    PubMed  Google Scholar 

  35. D. A. Lauffenburger and A. F. Horwitz (1996). Cell migration: A physically integrated molecular process. Cell 84:359-369.

    PubMed  Google Scholar 

  36. I. Rabinovitz and A. M. Mercurio (1997). The integrin α6β4 functions in carcinoma cell migration on laminin-1 by mediating the formation and stabilization of actin-containing motility structures. J. Cell. Biol. 139:1873-1884.

    PubMed  Google Scholar 

  37. F. Mainiero, A. Pepe, M. Yeon, Y. Ren, and F. G. Giancotti (1996). The intracellular functions of alpha6beta4 integrin are regulated by EGF. J. Cell. Biol. 134:241-253.

    PubMed  Google Scholar 

  38. I. Rabinovitz, A. Toker, and A. M. Mercurio (1999). Protein kinase C-dependent mobilization of the α6β4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic migration of carcinoma cells. J. Cell. Biol. 146:1147-1160.

    PubMed  Google Scholar 

  39. A. E. Aplin, A. K. Howe, and R. Juliano (1999). Cell adhesion molecules, signal transduction and cell growth. Curr. Opin. Cell. Biol. 11:737-744.

    PubMed  Google Scholar 

  40. P. J. Keely, J. K. Westwick, I. P. Whitehead, C. J. Der, and L. V. Parise (1997). Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 390:632-636.

    Google Scholar 

  41. A. Toker and L. C. Cantley (1997). Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387:673-676.

    PubMed  Google Scholar 

  42. S. Menard, E. Tagliabue, M. Campiglio, and S. M. Pupa (2000). Role of HER2 gene overexpression in breast carcinoma. J. Cell. Physiol. 182:150-162.

    PubMed  Google Scholar 

  43. R. Falcioni, A. Antonini, P. Nistico, S. Di Stefano, M. Crescenzi, P. G. Natali, and A. Sacchi (1997). α6β4 and α6β1 integrins associate with ErbB-2 in human carcinoma cell lines. Exp. Cell. Res. 236:76-85.

    PubMed  Google Scholar 

  44. D. Gambaletta, A. Marchetti, L. Benedetti, A. M. Mercurio, A. Sacchi, and R. Falcioni (2000). Cooperative signaling between α6β4 integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion. J. Biol. Chem. 275:10604-10610.

    PubMed  Google Scholar 

  45. G. G. Borisy and T. M. Svitkina (2000). Actin machinery: Pushing the envelope. Curr. Opin. Cell. Biol. 12:104-112.

    PubMed  Google Scholar 

  46. S. M. Schoenwaelder and K. Burridge (1999). Bidirectional signaling between the cytoskeleton and integrins. Curr. Opin. Cell. Biol. 11:274-286.

    PubMed  Google Scholar 

  47. L Mahadevan and P. Matsudaira (2000). Motility powered by supramolecular springs and ratchets. Science 288:95-100.

    PubMed  Google Scholar 

  48. E. E. Sander, S. van Delft, J. P. ten Klooster, T. Reid, R. A. van der Kammen, F. Michiels, and J. G. Collard (1998). Matrixdependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J. Cell. Biol. 143:1385-1398.

    PubMed  Google Scholar 

  49. D. H. van Weering, J. de Rooij, B. Marte, J. Downward, J. L. Bos, and B. M. Burgering (1998). Protein kinase B activation and lamellipodium formation are independent phosphoinositide 3-kinase-mediated events differentially regulated by endogenous Ras. Mol. Cell. Biol. 18:1802-1811.

    PubMed  Google Scholar 

  50. R. Meili, C. Ellsworth, S. Lee, T. B. Reddy, H. Ma, and R. A. Firtel (1999). Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium. EMBO J. 18:2092-2105.

    PubMed  Google Scholar 

  51. K. L. O'Connor, B. K. Nguyen, and A. M. Mercurio (2000). RhoA function in lamellae formation and migration is regulated by the α6β4 integrin and cAMP metabolism. J. Cell. Biol. 148:253-258.

    PubMed  Google Scholar 

  52. C. Laudanna, J. J. Campbell, and E. C. Butcher (1997). Elevation of intracellular cAMP inhibits RhoA activation and integrin-dependent leukocyte adhesion induced by chemoattractants. J. Biol. Chem. 272:24141-24144.

    PubMed  Google Scholar 

  53. K. Itoh, K. Yoshioka, H. Akedo, M. Uehata, T. Ishizaki, and S. Narumiya (1999). An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat. Med. 5:221-225.

    PubMed  Google Scholar 

  54. K. Yoshioka, F. Matsumura, H. Akedo, and K. Itoh (1998). Small GTP-binding protein Rho stimulates the actomyosin system, leading to invasion of tumor cells. J. Biol. Chem. 273:5146-5154.

    PubMed  Google Scholar 

  55. S. M. Frisch and H. Francis (1994). Disruption of epithelial cellmatrix interactions induces apoptosis. J. Cell. Biol. 124:619-626.

    PubMed  Google Scholar 

  56. N. Farrelly, Y. J. Lee, J. Oliver, C. Dive, and C. H. Streuli (1999). Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J. Cell. Biol. 144:1337-1348.

    PubMed  Google Scholar 

  57. M. A. Schwartz (1997). Integrins, oncogenes, and anchorage independence. J. Cell. Biol. 139:575-578.

    PubMed  Google Scholar 

  58. C. Hagios, A. Lochter, and M. J. Bissell (1998). Tissue architecture: The ultimate regulator of epithelial function? Philos. Trans. R. Soc. Lond. B. Biol. Sci. 353:857-870.

    PubMed  Google Scholar 

  59. J. M. Brown (1999). The hypoxic cell: A target for selective cancer therapy—eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res. 59:5863-5870.

    PubMed  Google Scholar 

  60. D. Hanahan and J. Folkman (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353-364.

    Article  PubMed  Google Scholar 

  61. B. R. Zetter (1998). Angiogenesis and tumor metastasis. Annu. Rev. Med. 49:407-424.

    PubMed  Google Scholar 

  62. S. R. Datta, A. Brunet, and M. E. Greenberg (1999). Cellular survival: A play in three Akts. Genes Dev. 13:2905-2927.

    PubMed  Google Scholar 

  63. J. M. Shields, K. Pruitt, A. McFall, A. Shaub, and C. J. Der (2000). Understanding Ras: 'it ain't over 'til it's over'. Trends Cell. Biol. 10:147-154.

    PubMed  Google Scholar 

  64. L. C. Cantley and B. G. Neel (1999). New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. U.S.A. 96:4240-4245.

    PubMed  Google Scholar 

  65. A. Toker and A. C. Newton (2000). Akt/Protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. J. Biol. Chem. 275:8271-8274.

    PubMed  Google Scholar 

  66. A. Khwaja, P. Rodriguez-Viciana, S. Wennstrom, P. H. Warne, and J. Downward (1997). Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16:2783-2793.

    PubMed  Google Scholar 

  67. V. Stambolic, A. Suzuki, J. L. de la Pompa, G. M. Brothers, C. Mirtsos, T. Sasaki, J. Ruland, J. M. Penninger, D. P. Siderovski, and T. W. Mak (1998). Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29-39.

    PubMed  Google Scholar 

  68. J. Downward (1998). Ras signalling and apoptosis. Curr. Opin. Genet. Dev. 8:49-54.

    PubMed  Google Scholar 

  69. A. Bellacosa, D. de Feo, A. K. Godwin, D. W. Bell, J. Q. Cheng, D. A. Altomare, M. Wan, L. Dubeau, G. Scambia, V. Masciullo, et al. (1995). Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 64:280-285.

    PubMed  Google Scholar 

  70. Z. Q. Yuan, M. Sun, R. I. Feldman, G. Wang, X. Ma, C. Jiang, D. Coppola, S. V. Nicosia, and J. Q. Cheng (2000). Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene 19:2324-2330.

    PubMed  Google Scholar 

  71. K. Jiang, D. Coppola, N. C. Crespo, S. V. Nicosia, A. D. Hamilton, S. M. Sebti, and J. Q. Cheng (2000). The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol. Cell. Biol. 20:139-148.

    PubMed  Google Scholar 

  72. K. Nakatani, D. A. Thompson, A. Barthel, H. Sakaue, W. Liu, R. J. Weigel, and R. A. Roth (1999). Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgenindependent prostate cancer lines. J. Biol. Chem. 274:21528-21532.

    PubMed  Google Scholar 

  73. L. M. Shaw, C. Chao, U. M. Wewer, and A. M. Mercurio (1996). Function of the integrin α6β1 in metastatic breast carcinoma cells assessed by expression of a dominant-negative receptor. Cancer Res. 56:959-963.

    PubMed  Google Scholar 

  74. A. Toker (2000). Protein kinases as mediators of phosphoinositide 3-kinase signaling. Mol. Pharmacol. 57:652-658.

    PubMed  Google Scholar 

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Mercurio, A.M., Bachelder, R.E., Chung, J. et al. Integrin Laminin Receptors and Breast Carcinoma Progression. J Mammary Gland Biol Neoplasia 6, 299–309 (2001). https://doi.org/10.1023/A:1011323608064

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