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Breast Cancer Research
Published in: Breast Cancer Research 3/2000

01-06-2000 | Review

Tyrosine kinase signalling in breast cancer: Tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer

Authors: Eran R Andrechek, William J Muller

Published in: Breast Cancer Research | Issue 3/2000

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Abstract

The ability of growth factors and their cognate receptors to induce mammary epithelial proliferation and differentiation is dependent on their ability to activate a number of specific signal transduction pathways. Aberrant expression of specific receptor tyrosine kinases (RTKs) has been implicated in the genesis of a significant proportion of sporadic human breast cancers. Indeed, mammary epithelial expression of activated RTKs such as ErbB2/neu in transgenic mice has resulted in the efficient induction of metastatic mammary tumours. Although it is clear from these studies that activation these growth factor receptor signalling cascades are directly involved in mammary tumour progression, the precise interaction of each of these signalling pathways in mammary tumourigenesis and metastasis remains to be elucidated. The present review focuses on the role of several specific signalling pathways that have been implicated as important components in RTK-mediated signal transduction. In particular, it focuses on two well characterized transgenic breast cancer models that carry the polyomavirus middle T(PyV mT) and neu oncogenes.
Literature
1.
Andrulis IL, Bull SB, Blackstein ME, 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: 1340-1349.PubMed
2.
Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse and survival with the amplification of the HER2/neu oncogene. Science. 1987, 235: 177-182. This paper implicated amplification status of ErbB2 as an important prognostic marker in human breast cancerCrossRefPubMed
3.
Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovaian cancer. Science. 1989, 244: 707-712.CrossRefPubMed
4.
Guy CT, Cardiff RD, Muller WJ: Activated neu induces rapid tumor progression. J Biol Chem. 1996, 271: 7673-7678. 10.1074/jbc.271.16.9567.CrossRefPubMed
5.
Lucchini F, Sacco MG, Hu N, et al: Early and multifocal tumors in breast, salivary, harderian and epididymal tissues developed in MMTY-Neu transgenic mice. Cancer Lett. 1992, 64: 203-209. 10.1016/0304-3835(92)90044-V.CrossRefPubMed
6.
Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 1988, 54: 105-115. This paper provided the first direct evidence that ErbB2 is causally involved in mammary tumour progression.CrossRefPubMed
7.
Siegel PM, Ryan ED, Cardiff RD, Muller WJ: 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. EMBO J. 1999, 18: 2149-2164. 10.1093/emboj/18.8.2149. This paper implicated coexpression of ErbB2 and ErbB3 as a prevalent event in mammary tumour progression.CrossRefPubMedPubMedCentral
8.
Lemoine NR, Staddon S, Dickson C, Barnes DM, Gullick WJ: Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer. Oncogene. 1990, 5: 237-239.PubMed
9.
Guy CT, Webster MA, Schaller M, et al: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA. 1992, 89: 10578-10582.CrossRefPubMedPubMedCentral
10.
Prigent SA, Gullick WJ: 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: 2831-2841. This paper provided evidence that erbB-3 is primarily involved in recruitment of the PI-3K signalling molecule.PubMedPubMedCentral
11.
Soltoff SP, Carraway KL, Prigent SA, Gullick WG, Cantley LC: ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 1994, 14: 3550-3558. Evidence is provided that the primary role of ErbB-3 is to recruit the PI-3K pathway to other EGF receptor family members.CrossRefPubMedPubMedCentral
12.
Brunet A, Bonni A, Zigmond MJ, et al: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999, 96: 857-868.CrossRefPubMed
13.
Dahl J, Jurczak A, Cheng LA, Baker DC, Benjamin TL: Evidence of a role for phosphatidylinositol 3-kinase activation in the blocking of apoptosis by polyomavirus middle T antigen. J Virol. 1998, 72: 3221-3226.PubMedPubMedCentral
14.
Franke TF, Kaplan DR, Cantley LC: PI3K: downstream AKTion blocks apoptosis. Cell. 1997, 88: 435-437. 10.1016/S0092-8674(00)81883-8.CrossRefPubMed
15.
Webster MA, Hutchinson JN, Rauh MJ, et al: Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. Mol Cell Biol. 1998, 18: 2344-2359.CrossRefPubMedPubMedCentral
16.
Guy CT, Cardiff RD, Muller WJ: Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992, 12: 954-961.CrossRefPubMedPubMedCentral
17.
18.
Cheng SH, Harvey R, Espino PC, et al: Peptide antibodies to the human c-fyn gene product demonstrate pp59c-fyn is capable of complex formation with the middle-T antigen of polyomavirus. EMBO J. 1988, 7: 3845-3855.PubMedPubMedCentral
19.
20.
Kornbluth S, Sudol M, Hanafusa H: Association of the polyomavirus middle-T antigen with c-yes protein. Nature. 1987, 325: 171-173. 10.1038/325171a0.CrossRefPubMed
21.
Kypta RM, Hemming A, Courtneidge SA: Identification and characterization of p59fyn (a src-like protein tyrosine kinase) in normal and polyoma virus transformed cells. EMBO J. 1988, 7: 3837-3844.PubMedPubMedCentral
22.
Luttrell DK, Lee A, Lansing TJ, et al: Involvement of pp60c-src with two major signaling pathways in human breast cancer. Proc Natl Acad Sci USA. 1994, 91: 83-87. Evidence is provided that links activation of the c-Src signalling molecule with human breast cancer cells that express elevated levels of epidermal growth factor receptor and ErbB2.CrossRefPubMedPubMedCentral
23.
Luttrell LM, Hawes BE, van Biesen T, et al: Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gbetagamma subunit-mediated activation of mitogen-activated protein kinases. J Biol Chem. 1996, 271: 19443-19450. 10.1074/jbc.271.21.12133.CrossRefPubMed
24.
Muthuswamy SK, Muller WJ: 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: 1801-1810.PubMed
25.
Muthuswamy SK, Muller WJ: Activation of the Src family of tyrosine kinases in mammary tumorigenesis. Adv Cancer Res. 1994, 64: 111-123.CrossRefPubMed
26.
Muthuswamy SK, Muller WJ: Direct and specific interaction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor. Oncogene. 1995, 11: 271-279.PubMed
27.
Muthuswamy SK, Siegel PM, Dankort DL, Webster MA, Muller WJ: Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. Mol Cell Biol. 1994, 14: 735-743. This paper suggested that the src tyrosine kinase is involved in ErbB2-mediated tumour progreession.CrossRefPubMedPubMedCentral
28.
Guy CT, Muthuswamy SK, Cardiff RD, Soriano P, Muller WJ: Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev. 1994, 8: 23-32. This paper provided direct genetic evidence that c-Src is a critical signalling pathway in mammary tumour progressionCrossRefPubMed
29.
Webster MK, Donoghue DJ: Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 1996, 15: 520-527.PubMedPubMedCentral
30.
Courtneidge SA, Heber A: An 81 kd protein complexed with middle T antigen and pp60c-src: a possible phosphatidylinositol kinase. Cell. 1987, 50: 1031-1037.CrossRefPubMed
31.
Alessi DR, Deak M, Casamayor A, et al: 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol. 1997, 7: 776-789. 10.1016/S0960-9822(06)00336-8.CrossRefPubMed
32.
Bellacosa A, Chan TO, Ahmed NN, et al: Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene. 1998, 17: 313-325. 10.1038/sj.onc.1201947.CrossRefPubMed
33.
Delcommenne M, Tan C, Gray V, 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 USA. 1998, 95: 11211-11216. 10.1073/pnas.95.19.11211.CrossRefPubMedPubMedCentral
34.
Eskew JD, Vanacore RM, Sung L, Morales PJ, Smith A: Cellular protection mechanisms against extracellular heme. heme- hemo-pexin, but not free heme, activates the N-terminal c-jun kinase. J Biol Chem. 1999, 274: 638-648. 10.1074/jbc.274.2.638.CrossRefPubMed
35.
Kane LP, Shapiro VS, Stokoe D, Weiss A: Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol. 1999, 9: 601-604. 10.1016/S0960-9822(99)80265-6.CrossRefPubMed
36.
Sizemore N, Leung S, Stark GR: Activation of phosphatidylinositol 3-kinase in response to interleukin- 1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol. 1999, 19: 4798-4805.CrossRefPubMedPubMedCentral
37.
Cardone MH, Roy N, Stennicke HR, et al: Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998, 282: 1318-1321. 10.1126/science.282.5392.1318.CrossRefPubMed
38.
Datta SR, Dudek H, Tao X, et al: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997, 91: 231-241. 10.1016/S0092-8674(00)80405-5.CrossRefPubMed
39.
Cheung A, Young L, Chen P, et al: Microcirculation and metastasis in a new mouse mammary tumor model system. Int J Oncol. 1997, 11: 235-241.
40.
Ben-Levy R, Paterson HF, Marshall CJ, Yarden Y: A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway. EMBO J. 1994, 13: 3302-3311.PubMedPubMedCentral
41.
Blaikie PA, Fournier E, Dilworth SM, et al: The role of the Shc phosphotyrosine interaction/phosphotyrosine binding domain and tyrosine phosphorylation sites in polyoma middle T antigen-mediated cell transformation. J Biol Chem. 1997, 272: 20671-20677. 10.1074/jbc.272.33.20671.CrossRefPubMed
42.
Campbell KS, Ogris E, Burke B, et al: Polyoma middle tumorantigen interacts with SHC protein via the NPTY (Asn-Pro-Thr-Tyr) motif in middle tumor antigen. Proc Natl Acad Sci USA. 1994, 91: 6344-6348.CrossRefPubMedPubMedCentral
43.
Dankort DL, Wang Z, Blackmore V, Moran MF, Muller WJ: Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation. Mol Cell Biol. 1997, 17: 5410-5425. This paper provided evidence of multiple functional redundant signalling pathways from the ErbB2 RTK.CrossRefPubMedPubMedCentral
44.
Dilworth SM, Brewster CE, Jones MD, et al: Transformation by polyoma virus middle T-antigen involves the binding and tyrosine phosphorylation of Shc. Nature. 1994, 367: 87-90. 10.1038/367087a0.CrossRefPubMed
45.
Gale NW, Kaplan S, Lowenstein EJ, Schlessinger J, Bar-Sagi D: Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature. 1993, 363: 88-92. 10.1038/363088a0.CrossRefPubMed
46.
Janes PW, Daly RJ, deFazio A, Sutherland RL: Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. Oncogene. 1994, 9: 3601-3608.PubMed
47.
Janes PW, Lackmann M, Church WB, et al: Structural determinants of the interaction between the erbB2 receptor and the Src homology 2 domain of Grb7. J Biol Chem. 1997, 272: 8490-8497. 10.1074/jbc.272.13.8490.CrossRefPubMed
48.
Niemann C, Brinkmann V, Spitzer E, 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: 533-545. 10.1083/jcb.143.2.533. This paper provided evidence that normal mammary gland morphogenesis is dependent on integration of both Met- and ErbB2-coupled signals.CrossRefPubMedPubMedCentral
49.
Pelicci G, Lanfrancone L, Grignani F, et al: A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell. 1992, 70: 93-104.CrossRefPubMed
50.
Ricci A, Lanfrancone L, Chiari R, et al: Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase. Oncogene. 1995, 11: 1519-1529.PubMed
51.
Chardin P, Camonis JH, Gale NW, et al: Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993, 260: 1338-1343.CrossRefPubMed
52.
Egan SE, Giddings BW, Brooks MW, et al: Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993, 363: 45-51. 10.1038/363045a0.CrossRefPubMed
53.
Li N, Batzer A, Daly R, et al: Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993, 363: 85-88. 10.1038/363085a0.CrossRefPubMed
54.
Lowenstein EJ, Daly RJ, Batzer AG, et al: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992, 70: 431-42.CrossRefPubMed
55.
Rozakis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D: The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature. 1993, 363: 83-85. 10.1038/363083a0.CrossRefPubMed
56.
Rozakis-Adcock M, McGlade J, Mbamalu G, 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: 689-692. 10.1038/360689a0.CrossRefPubMed
57.
Xie Y, Pendergast AM, Hung MC: Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu. J Biol Chem. 1995, 270: 30717-30724. 10.1074/jbc.270.30.18123.CrossRefPubMed
58.
Hallberg B, Rayter SI, Downward J: Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. J Biol Chem. 1994, 269: 3913-3916.PubMed
59.
60.
61.
McCormick F, Martin GA, Clark R, Bollag G, Polakis P: Regulation of ras p21 by GTPase activating proteins. Cold Spring Harb Symp Quant Biol. 1991, 56: 237-241.CrossRefPubMed
62.
Rodriguez-Viciana P, Marte BM, Warne PH, Downward J: Phosphatidylinositol 3' kinase: one of the effectors of Ras. Phil Trans R Soc Lond B Biol Sci. 1996, 351: 225-231; discussion 231-232.CrossRef
63.
Troppmair J, Bruder JT, Munoz H, et al: Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13- acetate requires Raf and is necessary for transformation. J Biol Chem. 1994, 269: 7030-7035.PubMed
64.
Warne PH, Viciana PR, Downward J: Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993, 364: 352-355. 10.1038/364352a0.CrossRefPubMed
65.
Zheng Y, Bagrodia S, Cerione RA: Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. J Biol Chem. 1994, 269: 18727-18730.PubMed
66.
Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P: Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987, 49: 465-475. This paper was one of the first to document cooperation of two independent oncogene-coupled signalling pathways in mammary tumour progression.CrossRefPubMed
67.
Cheng AM, Saxton TM, Sakai R, et al: Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell. 1998, 95: 793-803. This report provided evidence suggesting that the levels of Grb2/Ras pathway was critical in mammary tumour progression.CrossRefPubMed
68.
Rauh MJ, Blackmore V, Andrechek ER, et al: Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein. Mol Cell Biol. 1999, 19: 8169-8179.CrossRefPubMedPubMedCentral
Metadata
Title
Tyrosine kinase signalling in breast cancer: Tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer
Authors
Eran R Andrechek
William J Muller
Publication date
01-06-2000
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2000
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr56

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