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Oncogene Mediated Signal Transduction in Transgenic Mouse Models of Human Breast Cancer

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Biology of the Mammary Gland

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 480))

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References

  1. Hennighausen, L. and G.W. Robinson, Think globally, act locally: the making of a mouse mammary gland. Genes Dev, 1998. 12(4): 449–55.

    PubMed  CAS  Google Scholar 

  2. Vonderhaar, B.K. and A.E. Greco, Lobulo-alveolar development of mouse mammary glands is regulated by thyroid hormones.Endocrinology, 1979. 104 (2): 409–18.

    Article  PubMed  CAS  Google Scholar 

  3. Humphreys, R.C., et al., Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis. Development, 1996.122 (12): 4013–22.

    PubMed  CAS  Google Scholar 

  4. Coleman, S., G.B. Silberstein, and C.W. Daniel, Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for epidermal growth factor. Dev Biol, 1988. 127 (2): 304–15.

    Article  PubMed  CAS  Google Scholar 

  5. Sandgren, E.P., et al., Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell, 1990. 61 (6): 1121–35.

    Article  PubMed  CAS  Google Scholar 

  6. Sandgren, E.P., et al., Inhibition of mammary gland involution is associated with transforming growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice. Cancer Res, 1995. 55 (17): 3915–27.

    PubMed  CAS  Google Scholar 

  7. Matsui, Y., et al., Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice. Cell, 1990. 61 (6): 1147–55.

    Article  PubMed  CAS  Google Scholar 

  8. Jhappan, C., et al., TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell, 1990. 61 (6):1137–46.

    Article  PubMed  CAS  Google Scholar 

  9. Krane, I.M. and P. Leder, NDF/heregulin induces persistence of terminal end buds and adenocarcinomas in the mammary glands of transgenic mice. Oncogene, 1996.12 (8): 1781–8.

    PubMed  CAS  Google Scholar 

  10. Luetteke, N.C., et al., Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development, 1999. 126 (12): 2739–50.

    PubMed  CAS  Google Scholar 

  11. Fowler, K.J., et al., A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation. Proc Natl Acad Sci USA, 1995. 92 (5): 1465–9.

    PubMed  CAS  Google Scholar 

  12. Sebastian, J., et al., Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis. Cell Growth Differ, 1998. 9 (9): 777–85.

    PubMed  CAS  Google Scholar 

  13. Whitman, M., et al., Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature, 1988. 332 (6165): 644–6.

    Article  PubMed  CAS  Google Scholar 

  14. Prigent, SA. and W.J. Gullick, Identification of c-erbB-3 binding sites for phosphatidylinositol 3′-kinase and SHC using an EGF receptor/c-erbB-3 chimera. Embo J, 1994.13 (12): 2831–41.

    PubMed  CAS  Google Scholar 

  15. Soltoff, S.P., et al., ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol, 1994. 14 (6): 3550–8.

    PubMed  CAS  Google Scholar 

  16. Alessi, D.R., et al., Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha.Curr Biol, 1997. 7 (4): 261–9.

    Article  PubMed  CAS  Google Scholar 

  17. Alessi, D.R., et al., 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol, 1997.7 (10): 776–89.

    Article  PubMed  CAS  Google Scholar 

  18. Anderson, K.E., et al., Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. Curr Biol, 1998. 8 (12): 684–91.

    Article  PubMed  CAS  Google Scholar 

  19. Currie, R.A., et al., Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J, 1999. 337 (Pt3): 575–83.

    PubMed  CAS  Google Scholar 

  20. Delcommenne, M., et al., Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A, 1998. 95 (19): 11211–6.

    Article  PubMed  CAS  Google Scholar 

  21. Watton, S.J. and J. Downward, Akt/PKB localisation and 3’ phosphoinositide generation at sites of epithelial cell-matrix and cell-cell interaction. Curr Biol, 1999. 9 (8): 433–6.

    Article  PubMed  CAS  Google Scholar 

  22. Gibson, S., et al., Epidermal growth factor protects epithelial cells against Fas-induced apoptosis. Requirement for Akt activation. J Biol Chem, 1999. 274 (25):17612-8.

    Google Scholar 

  23. Kennedy, S.G., et al., Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria [In Process Citation]. Mol Cell Biol, 1999. 19 (8): 5800–10.

    PubMed  CAS  Google Scholar 

  24. Khwaja, A., et al., Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. Embo J, 1997. 16 (10): 2783–93.

    Article  PubMed  CAS  Google Scholar 

  25. Rodriguez-Viciana, P., et al., Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell, 1997. 89 (3): 457–67.

    PubMed  CAS  Google Scholar 

  26. Stambolic, V., et al., Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998. 95 (1): 29–39.

    Google Scholar 

  27. Staveley, B.E., et al., Genetic analysis of protein kinase B (AKT) in Drosophila. Curr Biol, 1998. 8 (10): 599–602.

    Article  PubMed  CAS  Google Scholar 

  28. Sun, H., et al., PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A, 1999. 96 (11): 6199–204.

    Article  PubMed  CAS  Google Scholar 

  29. Webster, M.A., et al., Requirement for both Shc and phosphatidylinositol 3’ kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. Mol Cell Biol, 1998. 18 (4): 2344–59.

    PubMed  CAS  Google Scholar 

  30. Datta, S.R., et al., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 1997. 91 (2): 231–41.

    Article  PubMed  CAS  Google Scholar 

  31. Cardone, M.H., et al., Regulation of cell death protease caspase-9 by phosphorylation. Science, 1998. 282 (5392): 1318–21.

    Article  PubMed  CAS  Google Scholar 

  32. Brunet, A., et al., Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 1999. 96 (6): 857–68.

    Article  PubMed  CAS  Google Scholar 

  33. Kane, L.P., et al., Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol, 1999. 9 (11): 601–4.

    Article  PubMed  CAS  Google Scholar 

  34. Yang, Y., et al., Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland. J Cell Biol, 1995. 131 (1): 215–26.

    Article  PubMed  CAS  Google Scholar 

  35. Niemann, C., et al., Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis. J Cell Biol, 1998. 143 (2): 533–45.

    Article  PubMed  CAS  Google Scholar 

  36. Janes, P.W., et al., Activation of the Ras signalling pathway in human breast cancer cells overexperssing erbB-2. Oncogene, 1994. 9(12): 3601–8.

    PubMed  CAS  Google Scholar 

  37. Dankort, D.L., et al., Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation. Mol Cell Biol, 1997. 17(9): 5410–25.

    PubMed  CAS  Google Scholar 

  38. Vijapurkar, U., K. Cheng, and J.G. Koland, Mutation of a Shc binding site tyrosine residue in ErbB3/MER3 blocks heregulin-dependent activation of mitogen-activated protein kinase. J Biol Chem, 1998. 273(33): 20996–1002.

    Article  PubMed  CAS  Google Scholar 

  39. Pelicci, G., et al., Constitutive phosphorylation of Shc proteins in human tumors. Oncogene, 1995. 11(5): 899–907.

    PubMed  CAS  Google Scholar 

  40. Daly, R.J., M.D. Binder, and R.L. Sutherland, Overexpression of the Grb2 gene in human breast cancer cell lines. Oncogen, 1994. 9(9): 2723–7.

    Google Scholar 

  41. Rozakis-Adcock, M., et al., Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature, 1992. 360(6405): 689–92.

    Article  PubMed  CAS  Google Scholar 

  42. Lowenstein, E.J., et al., The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell, 1992. 70(3): 431–42.

    Article  PubMed  CAS  Google Scholar 

  43. Skolnik, E.Y., et al., The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science, 1993. 260(5116): 1953–5.

    PubMed  CAS  Google Scholar 

  44. Rozakis-Adcock, M., et al., The SH2 and SH3 domains ofmammalian Grb2 couple the EGF receptor to the Ras activator mSos1 [see comments]. Nature, 1993. 363(6424): 83–5.

    Article  PubMed  CAS  Google Scholar 

  45. Egan, S.E., et al., Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation [see comments]. Nature, 1993. 363(6424): 45–51.

    Article  PubMed  CAS  Google Scholar 

  46. Gale, N.W., et al., Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras [see comments]. Nature, 1993. 363(6424): 88–92.

    Article  PubMed  CAS  Google Scholar 

  47. Li, N., et al., Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling [see comments]. Nature, 1993. 363(6424): 85–8.

    Google Scholar 

  48. Chardin, P., et al., Human Sosl: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science, 1993. 26(5112): 1338–43.

    Google Scholar 

  49. Skolnik, E.Y., et al., The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRSl and Shc: implications for insulin control of ras signalling. Embo J, 1993. 12(5): 1929–36.

    PubMed  CAS  Google Scholar 

  50. Yamauchi, T., et al., Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone. Nature, 1997. 390(6655): 91–6

    PubMed  CAS  Google Scholar 

  51. Pelicci, G., et al., A family of Shc related proteins with conserved PTB, CH1 and SH2 regions. Oncogene, 1996. 13(3): 633–41.

    PubMed  CAS  Google Scholar 

  52. Segatto, O., et al., Shc products are substrates of erbB-2 kinase. Oncogene, 1993. 8(8): 2105–12.

    PubMed  CAS  Google Scholar 

  53. Hashimoto, A., et al., Shc Regulates Epidermal Growth Factor-induced Activation of the JNK Signaling Pathway. J Biol Chem, 1999. 274(29): 20139–20143.

    Article  PubMed  CAS  Google Scholar 

  54. Gotoh, N., M. Toyoda, and M. Shibuya, Tyrosine phosphorylation sites at amino acids 239 and 240 of Shc are involved in epidermal growth factor-induced mitogenic signaling that is distinct from Radmitogen-activated protein kinase activation. Mol Cell Biol, 1997. 17(4): 1824–31.

    PubMed  CAS  Google Scholar 

  55. Harmer, S.L. and A.L. DeFranco, Shc contains two Grb2 binding sites needed for efficient formation of complexes with SOS in B lymphocytes. Mol Cell Biol, 1997. 17(7): 4087–95.

    PubMed  CAS  Google Scholar 

  56. van der Geer, P., et al., The Shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (Y239/240) that mediate protein-protein interactions. Curr Biol, 1996. 6(11): 1435–44.

    PubMed  Google Scholar 

  57. Gotoh, N., A. Tojo, and M. Shibuya, A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3. Embo J, 1996. 15(22): 6197–204.

    PubMed  CAS  Google Scholar 

  58. Jelinek, T., et al., RAS and RAF-1 form a signalling complex with MEK-1 but not MEK-2. Mol Cell Biol, 1994. 14(12): 8215–8.

    Google Scholar 

  59. Moodie, S.A., et al., Association of MEK1 with p21ras.GMPPNP is dependent on B-Raf. Mol Cell Biol, 1994, 14(11). 7153–62.

    PubMed  CAS  Google Scholar 

  60. Moodie, SA. and A. Wolfman, The 3Rs of life: Ras, Raf and growth regulation. Trends Genet, 1994, 10(2). 44–8.

    Article  PubMed  CAS  Google Scholar 

  61. Marshall, M.S., Ras target proteins in eukaryotic cells. Faseb J, 1995. 9(13): 1311–8.

    PubMed  CAS  Google Scholar 

  62. Whitmarsh, A.J., et al., Integration of MAP kinase signal transduction pathways at the serum response element. Science, 1995. 269(5222): 403–7.

    PubMed  CAS  Google Scholar 

  63. Deng, T. and M. Karin, c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK. Nature, 1994. 371(6493): 171–5.

    Article  PubMed  CAS  Google Scholar 

  64. Hipskind, R.A., M. Baccarini, and A. Nordheim, Transient activation of RAF-1, MEK, and ERK2 coincides kinetically with ternary complex factor phosphorylation and immediate-early gene promoter activity in vivo. Mol Cell Biol, 1994. 14(9): 6219–31.

    PubMed  CAS  Google Scholar 

  65. Treisman, R., Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev, 1994. 4(1): 96–101.

    Article  PubMed  CAS  Google Scholar 

  66. Luttrell, D.K., et al., Involvement of pp60c-src with two major signaling pathways in human breast cancer. Proc Natl Acad Sci U S A, 1994. 91(1): 83–7.

    PubMed  CAS  Google Scholar 

  67. Muthuswamy, S.K., et al., Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. Mol Cell Biol, 1994. 14(1): 735–43.

    PubMed  CAS  Google Scholar 

  68. Muthuswamy, S.K. and W.J. Muller, Activation of the Src family of tyrosine kinases in mammary tumorigenesis. Adv Cancer Res, 1994. 64: 111–23.

    PubMed  CAS  Google Scholar 

  69. Muthuswamy, S.K. and W.J. Muller, Activation of Src family kinases in Neu-induced mammary tumors correlates with their association with distinct sets of tyrosine phosphorylated proteins in vivo. Oncogene, 1995. 11(9): 1801–10.

    PubMed  CAS  Google Scholar 

  70. Muthuswamy, S.K. and W.J. Muller, Direct and specific interaction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor. Oncogene, 1995. 11(2): 271–9.

    PubMed  CAS  Google Scholar 

  71. Ponzetto, C., et al., A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell, 1994. 77(2): 261–71.

    Article  PubMed  CAS  Google Scholar 

  72. Courtneidge, SA., et al., Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor. Embo J, 1993. 12(3): 943–50.

    PubMed  CAS  Google Scholar 

  73. Lee, R.J., et al., pp60(v-src) induction of cyclin D1 requires collaborative interactions between the extracellular signal-regulated kinase, p38, and Jun kinase pathways. A role for cAMP response element-binding protein and activating transcription factor-2 in pp60(v-src) signaling in breast cancer cells. J Biol Chem, 1999. 274(11): 7341–50.

    Article  PubMed  CAS  Google Scholar 

  74. Calalb, M.B., T.R. Polte, and S.K. Hanks, Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol, 1995. 15(2): 954–63.

    PubMed  CAS  Google Scholar 

  75. Klinghoffer, R.A., et al., Src family kinases are required for integrin but not PDGFR signal transduction. Mol Cell Biol, 1999, 18(9): 2459–71.

    CAS  Google Scholar 

  76. Lo, S.S., et al., Inhibition of focal contact formation in cells transformed by p185neu. Mol Carcinog, 1999, 25()2: 150–4.

    Article  PubMed  CAS  Google Scholar 

  77. Oktay, M., et al., Integrin-mediated activation of focal adhesion kinase is required for signaling to Jun NH2-terminal kinase and progression through the G1 phase of the cell cycle. J Cell Biol, 1999. 145(7): 1461–9.

    Article  PubMed  CAS  Google Scholar 

  78. Schaller, M.D., et al., Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol, 1994. 14(3): 1680–8.

    PubMed  CAS  Google Scholar 

  79. Andrulis, I.L., et al., neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol, 1998. 16(4): 1340–9.

    PubMed  CAS  Google Scholar 

  80. Slamon, D.J., Clark, G.M., Wong, S.G., Levin, W.J., Ullrich, A. and McGuire, W.L., Human breast cancer: correlation of relapse and survival with the amplification of the HER2/neu oncogene. Science, 1987. 235: 177–182.

    PubMed  CAS  Google Scholar 

  81. Slamon, D.J., Godolphin, W., Jones, L.A., Holt, J.A., Wong, S.G., Keith, D.E., Levin, W.J., Stuart, S.G., Udove, J., Ullrich, A., and Press, M.F., Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 1989. 244: 707–712.

    PubMed  CAS  Google Scholar 

  82. Guy, C.T., R.D. Cardiff, and W.J. Muller, Activated neu induces rapid tumor progression. J Biol Chem, 1996. 271(13): 7673–8.

    PubMed  CAS  Google Scholar 

  83. Bouchard, L., et al., Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell, 1989. 57(6): 931–6.

    Article  PubMed  CAS  Google Scholar 

  84. Muller, W.J., et al., Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell, 1988. 54(1): 105–15.

    Article  PubMed  CAS  Google Scholar 

  85. Lemoine, N.R., et al., Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer. Oncogene, 1990. 5(2): 237–9.

    PubMed  CAS  Google Scholar 

  86. Zoll, B., et al., Alterations of the c-erbB2 gene in human breast cancer. J Cancer Res Clin Oncol, 1992. 11(6): 468–73.

    Google Scholar 

  87. Guy, C.T., et al., Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A, 1992. 89(22): 10578–82.

    PubMed  CAS  Google Scholar 

  88. Siegel, P.M. and W.J. Muller, Mutations affecting conserved cysteine residues within the extracellular domain of Neu promote receptor dimerization and activation. Proc Natl Acad Sci U S A, 1996. 93(17): 8878–83.

    Article  PubMed  CAS  Google Scholar 

  89. Siegel, P.M., et al., Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer [In Process Citation]. Embo J, 1999. 18(8): 2149–64.

    Article  PubMed  CAS  Google Scholar 

  90. Siegel, P.M., et al., Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol Cell Biol, 1994. 14(11): 7068–77.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. The Institute for Molecular Biology & Biotechnology, McMaster University, Hamilton, Ontario

    Peter M. Siegel, David L. Dankort & William J. Muller

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  1. Peter M. Siegel
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  2. David L. Dankort
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  1. Utrecht University, Utrecht, The Netherlands

    Jan A. Mol

  2. Hannah Research Institute, Ayr, Scotland, UK

    Roger A. Clegg

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Siegel, P.M., Dankort, D.L., Muller, W.J. (2002). Oncogene Mediated Signal Transduction in Transgenic Mouse Models of Human Breast Cancer. In: Mol, J.A., Clegg, R.A. (eds) Biology of the Mammary Gland. Advances in Experimental Medicine and Biology, vol 480. Springer, Boston, MA. https://doi.org/10.1007/0-306-46832-8_23

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