Profiling the tyrosine phosphoproteome of different mouse mammary tumour models reveals distinct, model-specific signalling networks and conserved oncogenic pathways
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- 作者：Naveid A Ali ; Jianmin Wu ; Falko Hochgr?fe ; Howard Chan…
- 刊名：Breast Cancer Research
- 出版年：2014
- 出版时间：October 2014
- 年：2014
- 卷：16
- 期：5
- 全文大小：3,322 KB
- 参考文献：1. Yarden Y, Pines G: The ERBB network: at last, cancer therapy meets systems biology. / Nat Rev Cancer 2012, 12:553-63. CrossRef
2. Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, Hedvat CV, Traina TA, Solit D, Gerald W, Moynahan ME: PIK3CA mutation associates with improved outcome in breast cancer. / Clin Cancer Res 2009, 15:5049-059. CrossRef
3. Creedon H, Brunton VG: Src kinase inhibitors: promising cancer therapeutics? / Crit Rev Oncog 2012, 17:145-59. CrossRef
4. Celebi JT, Adams SJ, Aydin IT: GAB2—a scaffolding protein in cancer. / Mol Cancer Res 2012, 10:1265-270. CrossRef
5. Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, Ardlie KG, Auclair D, Bautista-Pi?a V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher SE, Stransky N, / et al: Sequence analysis of mutations and translocations across breast cancer subtypes. / Nature 2012, 486:405-09. CrossRef
6. Bentires-Alj M, Gil SG, Chan R, Wang ZC, Wang Y, Imanaka N, Harris LN, Richardson A, Neel BG, Gu H: A role for the scaffolding adapter GAB2 in breast cancer. / Nat Med 2006, 12:114-21. CrossRef
7. Brough R, Frankum JR, Sims D, Mackay A, Mendes-Pereira AM, Bajrami I, Costa-Cabral S, Rafiq R, Ahmad AS, Cerone MA, Natrajan R, Sharpe R, Shiu KK, Wetterskog D, Dedes KJ, Lambros MB, Rawjee T, Linardopoulos S, Reis-Filho JS, Turner NC, Lord CJ, Ashworth A: Functional viability profiles of breast cancer. / Cancer Discov 2011, 1:260-73. CrossRef
8. Ursini-Siegel J, Schade B, Cardiff RD, Muller WJ: Insights from transgenic mouse models of ERBB2-induced breast cancer. / Nat Rev Cancer 2007, 7:389-97. CrossRef
9. Yuan W, Stawiski E, Janakiraman V, Chan E, Durinck S, Edgar KA, Kljavin NM, Rivers CS, Gnad F, Roose-Girma M, Haverty PM, Fedorowicz G, Heldens S, Soriano RH, Zhang Z, Wallin JJ, Johnson L, Merchant M, Modrusan Z, Stern HM, Seshagiri S: Conditional activation of Pik3ca H1047R in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. / Oncogene 2012, 32:318-26. CrossRef
10. Hudis CA: Trastuzumab—mechanism of action and use in clinical practice. / N Engl J Med 2007, 357:39-1. CrossRef
11. Brenton JD, Carey LA, Ahmed AA, Caldas C: Molecular classification and molecular forecasting of breast cancer: ready for clinical application? / J Clin Oncol 2005, 23:7350-360. CrossRef
12. Rakha EA, Reis-Filho JS, Ellis IO: Basal-like breast cancer: a critical review. / J Clin Oncol 2008, 26:2568-581. CrossRef
13. Graveel CR, DeGroot JD, Su Y, Koeman J, Dykema K, Leung S, Snider J, Davies SR, Swiatek PJ, Cottingham S, Watson MA, Ellis MJ, Sigler RE, Furge KA, Vande Woude GF: Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer. / Proc Natl Acad Sci U S A 2009, 106:12909-2914. CrossRef
14. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. / Clin Cancer Res 2004, 10:5367-374. CrossRef
15. Ponzo MG, Lesurf R, Petkiewicz S, O’Malley FP, Pinnaduwage D, Andrulis IL, Bull SB, Chughtai N, Zuo D, Souleimanova M, Germain D, Omeroglu A, Cardiff RD, Hallett M, Park M: Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. / Proc Natl Acad Sci U S A 2009, 106:12903-2908. CrossRef
16. Hochgr?fe F, Zhang L, O’Toole SA, Browne BC, Pinese M, Porta Cubas A, Lehrbach GM, Croucher DR, Rickwood D, Boulghourjian A, Shearer R, Nair R, Swarbrick A, Faratian D, Mullen P, Harrison DJ, Biankin AV, Sutherland RL, Raftery MJ, Daly RJ: Tyrosine phosphorylation profiling reveals the signaling network characteristics of basal breast cancer cells. / Cancer Res 2010, 70:9391-401. CrossRef
17. Grigoriadis A, Mackay A, Noel E, Wu PJ, Natrajan R, Frankum J, Reis-Filho JS, Tutt A: Molecular characterisation of cell line models for triple-negative breast cancers. / BMC Genomics 2012, 13:619. CrossRef
18. Vargo-Gogola T, Rosen JM: Modelling breast cancer: one size does not fit all. / Nat Rev Cancer 2007, 7:659-72. CrossRef
19. Fluck MM, Schaffhausen BS: Lessons in signaling and tumorigenesis from polyomavirus middle T antigen. / Microbiol Mol Biol Rev 2009, 73:542-63. CrossRef
20. Webster MA, Hutchinson JN, Rauh MJ, Muthuswamy SK, Anton M, Tortorice CG, Cardiff RD, Graham FL, Hassell JA, Muller WJ: Requirement for both Shc and phosphatidylinositol 3-kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. / Mol Cell Biol 1998, 18:2344-359.
21. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM: Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. / Genome Biol 2007, 8:R76. CrossRef
22. Herschkowitz JI, Zhao W, Zhang M, Usary J, Murrow G, Edwards D, Knezevic J, Greene SB, Darr D, Troester MA, Hilsenbeck SG, Medina D, Perou CM, Rosen JM: Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells. / Proc Natl Acad Sci U S A 2012, 109:2778-783. CrossRef
23. Jerry DJ, Kittrell FS, Kuperwasser C, Laucirica R, Dickinson ES, Bonilla PJ, Butel JS, Medina D: A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. / Oncogene 2000, 19:1052-058. CrossRef
24. Bennett CN, Green JE: Unlocking the power of cross-species genomic analyses: identification of evolutionarily conserved breast cancer networks and validation of preclinical models. / Breast Cancer Res 2008, 10:213. CrossRef
25. Bennett CN, Green JE: Genomic analyses as a guide to target identification and preclinical testing of mouse models of breast cancer. / Toxicol Pathol 2010, 38:88-5. CrossRef
26. Nair R, Roden DL, Teo WS, McFarland A, Junankar S, Ye S, Nguyen A, Yang J, Nikolic I, Hui M, Morey A, Shah J, Pfefferle AD, Usary J, Selinger C, Baker LA, Armstrong N, Cowley MJ, Naylor MJ, Ormandy CJ, Lakhani SR, Herschkowitz JI, Perou CM, Kaplan W, O’Toole SA, Swarbrick A: c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer. / Oncogene 2013, 33:3992-002. CrossRef
27. Bargmann CI, Weinberg RA: Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. / Proc Natl Acad Sci U S A 1988, 85:5394-398. CrossRef
28. Van Parijs L, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D: Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. / Immunity 1999, 11:281-88. CrossRef
29. Swarbrick A, Roy E, Allen T, Bishop JM: Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. / Proc Natl Acad Sci U S A 2008, 105:5402-407. CrossRef
30. Welm AL, Kim S, Welm BE, Bishop JM: MET and MYC cooperate in mammary tumorigenesis. / Proc Natl Acad Sci U S A 2005, 102:4324-329. CrossRef
31. Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D, Medina D, Tsimelzon A, Hilsenbeck S, Green JE, Michalowska AM, Rosen JM: Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. / Cancer Res 2008, 68:4674-682. CrossRef
32. 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, 12:954-61.
33. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M: Andromeda: a peptide search engine integrated into the MaxQuant environment. / J Proteome Res 2011, 10:1794-805. CrossRef
34. Troyanskaya O, Cantor M, Sherlock G, Brown P, Hastie T, Tibshirani R, Botstein D, Altman RB: Missing value estimation methods for DNA microarrays. / Bioinformatics 2001, 17:520-25. CrossRef
35. Strimmer K: A unified approach to false discovery rate estimation. / BMC Bioinformatics 2008, 9:303. CrossRef
36. Breiman L: Random forests. / Mach Learn 2001, 45:5-2. CrossRef
37. Cowley MJ, Pinese M, Kassahn KS, Waddell N, Pearson JV, Grimmond SM, Biankin AV, Hautaniemi S, Wu J: PINA v2.0: mining interactome modules. / Nucleic Acids Res 2012, 40:D862–D865. CrossRef
38. Wu J, Vallenius T, Ovaska K, Westermarck J, M?kel? TP, Hautaniemi S: Integrated network analysis platform for protein-protein interactions. / Nat Methods 2009, 6:75-7. CrossRef
39. Hornbeck PV, Kornhauser JM, Tkachev S, Zhang B, Skrzypek E, Murray B, Latham V, Sullivan M: PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. / Nucleic Acids Res 2012, 40:D261–D270. CrossRef
40. Shi G, Zhang L, Jiang T: MSOAR 2.0: incorporating tandem duplications into ortholog assignment based on genome rearrangement. / BMC Bioinformatics 2010, 11:10. CrossRef
41. Wu J, Mao X, Cai T, Luo J, Wei L: KOBAS server: a web-based platform for automated annotation and pathway identification. / Nucleic Acids Res 2006, 34:W720–W724. CrossRef
42. Xie C, Mao X, Huang J, Ding Y, Wu J, Dong S, Kong L, Gao G, Li CY, Wei L: KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. / Nucleic Acids Res 2011, 39:W316–W322. CrossRef
43. Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. / J R Stat Soc Series B Methodol 1995, 57:289-00.
44. Janes PW, Daly RJ, deFazio A, Sutherland RL: Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. / Oncogene 1994, 9:3601-608.
45. Olshen AB, Venkatraman ES, Lucito R, Wigler M: Circular binary segmentation for the analysis of array-based DNA copy number data. / Biostatistics 2004, 5:557-72. CrossRef
46. Bioconductor Open Source Software for Bioinformatics: DNAcopy: DNA copy number data analysis. [http://www.bioconductor.org/packages/release/bioc/html/DNAcopy.html] (accessed 15 September 2014).
47. R Project for Statistical Computing: R-2.15.2. [http://cran.r-project.org/bin/windows/base/old/2.15.2/] (accessed 15 September 2014).
48. Brummer T, Schramek D, Hayes VM, Bennett HL, Caldon CE, Musgrove EA, Daly RJ: Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein. / J Biol Chem 2006, 281:626-37. CrossRef
49. PhosphoSitePlus. [http://www.phosphosite.org/] (accessed 15 September 2014).
50. 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, 8:23-2. CrossRef
51. Hellman A, Zlotorynski E, Scherer SW, Cheung J, Vincent JB, Smith DI, Trakhtenbrot L, Kerem B: A role for common fragile site induction in amplification of human oncogenes. / Cancer Cell 2002, 1:89-7. CrossRef
52. Xu K, Usary J, Kousis PC, Prat A, Wang DY, Adams JR, Wang W, Loch AJ, Deng T, Zhao W, Cardiff RD, Yoon K, Gaiano N, Ling V, Beyene J, Zacksenhaus E, Gridley T, Leong WL, Guidos CJ, Perou CM, Egan SE: Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. / Cancer Cell 2012, 21:626-41. CrossRef
53. Smolen GA, Muir B, Mohapatra G, Barmettler A, Kim WJ, Rivera MN, Haserlat SM, Okimoto RA, Kwak E, Dahiya S, Garber JE, Bell DW, Sgroi DC, Chin L, Deng CX, Haber DA: Frequent met oncogene amplification in a Brca1 / Trp53 mouse model of mammary tumorigenesis. / Cancer Res 2006, 66:3452-455. CrossRef
54. Abella JV, Peschard P, Naujokas MA, Lin T, Saucier C, Urbé S, Park M: Met/hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation. / Mol Cell Biol 2005, 25:9632-645. CrossRef
55. Croucher DR, Hochgr?fe F, Zhang L, Liu L, Lyons RJ, Rickwood D, Tactacan CM, Browne BC, Ali N, Chan H, Shearer R, Gallego-Ortega D, Saunders DN, Swarbrick A, Daly RJ: Involvement of Lyn and the atypical kinase SgK269/PEAK1 in a basal breast cancer signaling pathway. / Cancer Res 2013, 73:1969-980. CrossRef
56. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, MacNeill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. / Cell 2007, 131:1190-203. CrossRef
57. Hodgson JG, Malek T, Bornstein S, Hariono S, Ginzinger DG, Muller WJ, Gray JW: Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. / Cancer Res 2005, 65:9695-704. CrossRef
58. Sáez R, Molina MA, Ramsey EE, Rojo F, Keenan EJ, Albanell J, Lluch A, García-Conde J, Baselga J, Clinton GM: p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. / Clin Cancer Res 2006, 12:424-31. CrossRef
59. Pedersen K, Angelini PD, Laos S, Bach-Faig A, Cunningham MP, Ferrer-Ramón C, Luque-García A, García-Castillo J, Parra-Palau JL, Scaltriti M, Ramón y Cajal S, Baselga J, Arribas J: A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis. / Mol Cell Biol 2009, 29:3319-331. CrossRef
60. Zhang X, Pickin KA, Bose R, Jura N, Cole PA, Kuriyan J: Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. / Nature 2007, 450:741-44. CrossRef
61. Nagashima T, Ushikoshi-Nakayama R, Suenaga A, Ide K, Yumoto N, Naruo Y, Takahashi K, Saeki Y, Taiji M, Tanaka H, Tsai SF, Hatakeyama M: Mutation of epidermal growth factor receptor is associated with MIG6 expression. / FEBS J 2009, 276:5239-251. CrossRef
62. Wang Z, Raines LL, Hooy RM, Roberson H, Leahy DJ, Cole PA: Tyrosine phosphorylation of Mig6 reduces its inhibition of the epidermal growth factor receptor. / ACS Chem Biol 2013, 8:2372-376. CrossRef
63. Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-Cardo C, Beug H, Grünert S: Autocrine PDGFR signaling promotes mammary cancer metastasis. / J Clin Invest 2006, 116:1561-570. CrossRef
64. Lemmon MA, Schlessinger J: Cell signaling by receptor tyrosine kinases. / Cell 2010, 141:1117-134. CrossRef
65. Cuevas BD, Lu Y, Mao M, Zhang J, LaPushin R, Siminovitch K, Mills GB: Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. / J Biol Chem 2001, 276:27455-7461. CrossRef
66. Cook RS, Garrett JT, Sánchez V, Stanford JC, Young C, Chakrabarty A, Rinehart C, Zhang Y, Wu Y, Greenberger L, Horak ID, Arteaga CL: ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. / Cancer Res 2011, 71:3941-951. CrossRef
67. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, / et al: The clonal and mutational evolution spectrum of primary triple-negative breast cancers. / Nature 2012, 486:395-99.
68. Network CGA: Comprehensive molecular portraits of human breast tumours. / Nature 2012, 490:61-0. CrossRef
69. Knight JF, Lesurf R, Zhao H, Pinnaduwage D, Davis RR, Saleh SM, Zuo D, Naujokas MA, Chughtai N, Herschkowitz JI, Prat A, Mulligan AM, Muller WJ, Cardiff RD, Gregg JP, Andrulis IL, Hallett MT, Park M: Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer. / Proc Natl Acad Sci U S A 2013, 110:E1301–E1310. CrossRef
70. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu TL, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J: Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. / Sci Signal 2009, 2:ra73.
71. Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J, Wang Y, Gu TL, Ale?kovi? M, LeRoy G, Kang Y, Kang HB, Seo JH, Shan C, Jin P, Gong W, Lonial S, Arellano ML, Khoury HJ, Chen GZ, Shin DM, Khuri FR, Boggon TJ, Kang S, He C, Chen J: Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. / Nat Commun 2013, 4:1790. CrossRef
72. Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, / et al: Melanoma genome sequencing reveals frequent PREX2 mutations. / Nature 2012, 485:502-06. - 作者单位：Naveid A Ali (1)
Jianmin Wu (1)
Falko Hochgr?fe (1) (2)
Howard Chan (1) (3)
Radhika Nair (1)
Sunny Ye (1)
Luxi Zhang (1) (3)
Ruth J Lyons (1)
Mark Pinese (1)
Hong Ching Lee (1)
Nicola Armstrong (4)
Christopher J Ormandy (1)
Susan J Clark (1)
Alexander Swarbrick (1)
Roger J Daly (1) (3)
1. Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Sydney, NSW, 2010, Australia
2. Current Address: Junior Research Group Pathoproteomics, Competence Center in Functional Genomics, University of Greifswald, F.-L.-Jahnstr. 15, Greifswald, 17489, Germany
3. Current Address: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Level 1, Building 77, Clayton, VIC, 3800, Australia
4. School of Mathematics and Statistics, The University of Sydney, Room 637, Carslaw Building F07, Sydney, NSW, 2006, Australia - ISSN：1465-5411
文摘
Introduction Although aberrant tyrosine kinase signalling characterises particular breast cancer subtypes, a global analysis of tyrosine phosphorylation in mouse models of breast cancer has not been undertaken to date. This may identify conserved oncogenic pathways and potential therapeutic targets. Methods We applied an immunoaffinity/mass spectrometry workflow to three mouse models: murine stem cell virus-Neu, expressing truncated Neu, the rat orthologue of human epidermal growth factor receptor 2, Her2 (HER2); mouse mammary tumour virus-polyoma virus middle T antigen (PyMT); and the p53 ??/sup> transplant model (p53). Pathways and protein–protein interaction networks were identified by bioinformatics analysis. Molecular mechanisms underpinning differences in tyrosine phosphorylation were characterised by Western blot analysis and array comparative genomic hybridisation. The functional role of mesenchymal–epithelial transition factor (Met) in a subset of p53-null tumours was interrogated using a selective tyrosine kinase inhibitor (TKI), small interfering RNA (siRNA)–mediated knockdown and cell proliferation assays. Results The three models could be distinguished on the basis of tyrosine phosphorylation signatures and signalling networks. HER2 tumours exhibited a protein–protein interaction network centred on avian erythroblastic leukaemia viral oncogene homologue 2 (Erbb2), epidermal growth factor receptor and platelet-derived growth factor receptor α, and they displayed enhanced tyrosine phosphorylation of ERBB receptor feedback inhibitor 1. In contrast, the PyMT network displayed significant enrichment for components of the phosphatidylinositol 3-kinase signalling pathway, whereas p53 tumours exhibited increased tyrosine phosphorylation of Met and components or regulators of the cytoskeleton and shared signalling network characteristics with basal and claudin-low breast cancer cells. A subset of p53 tumours displayed markedly elevated cellular tyrosine phosphorylation and Met expression, as well as Met gene amplification. Treatment of cultured p53-null cells exhibiting Met amplification with a selective Met TKI abrogated aberrant tyrosine phosphorylation and blocked cell proliferation. The effects on proliferation were recapitulated when Met was knocked down using siRNA. Additional subtypes of p53 tumours exhibited increased tyrosine phosphorylation of other oncogenes, including Peak1/SgK269 and Prex2. Conclusion This study provides network-level insights into signalling in the breast cancer models utilised and demonstrates that comparative phosphoproteomics can identify conserved oncogenic signalling pathways. The Met-amplified, p53-null tumours provide a new preclinical model for a subset of triple-negative breast cancers.