Molecular and Transcriptional Signatures for ErbB2-Induced Invasion

Abstract

Purpose of Review

Invasion and metastasis are the most fatal activities connected to ErbB2. Current ErbB2-targeting therapies are highly efficient against early stage breast cancer, but often fail to cure the advanced cases. It is estimated that the majority of ErbB2-positive, invasive breast cancers are either intrinsically resistant to the current antibody-based therapy or can develop into resistant disease with high risk of metastasis. Local invasion is a prerequisite for metastatic dissemination. Here, we introduce and summarize the latest mechanistic knowledge of how ErbB2 activation can lead to invasion and spreading of breast cancer cells.

Recent Findings

In this review, we focus on the recent research in the molecular and cellular changes that initiate and maintain ErbB2-induced invasion. These comprise mechanisms that can promote cell migration and those that activate the extracellular degradome, as well as the involvement of lysosomes. We also discuss epithelial-to-mesenchymal transition and circulating tumor cells and what is currently known about their role in invasive, ErbB2-positive breast cancer.

Summary

The activation of invasion in ErbB2-positive breast cancer cells is accomplished by initiation of invasion-promoting transcriptional programs, including activation of transcription factors such as myeloid zinc finger 1 (MZF1) and Ets1 that leads to changes in the expression of genes that can drive and maintain the invasive and metastatic cellular phenotype. Increasing our understanding of the downstream components of the ErbB2 signaling, especially those that regulate its invasive function, can contribute to the development of novel treatments that benefit patients with advanced and therapy-resistant ErbB2-positive breast cancer.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. 1.

    Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 2015;34(1):157–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells. 1998;16(6):413–28.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    • Brix DM, Clemmensen KK, Kallunki T. When good turns bad: regulation of invasion and metastasis by ErbB2 receptor tyrosine kinase. Cell. 2014;3(1):53–78. The current review can be considered as an independent continuation of this earlier review. Thus, many things referred in it have been replaced with the latest information from the field.

    Article  CAS  Google Scholar 

  4. 4.

    Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell. 2003;11(2):495–505.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19(13):3159–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Klapper LN, Glathe S, Vaisman N, Hynes NE, Andrews GC, Sela M, et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A. 1999;96(9):4995–5000.

  7. 7.

    Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16(7):1647–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996;16(10):5276–87.

  9. 9.

    Jones RB, Gordus A, Krall JA, MacBeath G. A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature. 2006;439(7073):168–74.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Baulida J, Kraus MH, Alimandi M, Di Fiore PP, Carpenter G. All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem. 1996;271(9):5251–7.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem. 1999;274(13):8865–74.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Lenferink AE, Pinkas-Kramarski R, van de Poll ML, van Vugt MJ, Klapper LN, Tzahar E, et al. Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J. 1998;17(12):3385–97.

  13. 13.

    Hsieh MY, Yang S, Raymond-Stinz MA, Steinberg S, Vlachos DG, Shu W, et al. Stochastic simulations of ErbB homo and heterodimerisation: potential impacts of receptor conformational state and spatial segregation. IET Syst Biol. 2008;2(5):256–72.

    Article  PubMed  Google Scholar 

  14. 14.

    Lonardo F, Di Marco E, King CR, Pierce JH, Segatto O, Aaronson SA, et al. The normal erbB-2 product is an atypical receptor-like tyrosine kinase with constitutive activity in the absence of ligand. New Biol. 1990;2(11):992–1003.

    CAS  PubMed  Google Scholar 

  15. 15.

    Dankort D, Jeyabalan N, Jones N, Dumont DJ, Muller WJ. Multiple ErbB-2/Neu phosphorylation sites mediate transformation through distinct effector proteins. J Biol Chem. 2001;276(42):38921–8.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol. 2004;44:195–217.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 1997;410(1):83–6.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3(2):224–37.

  19. 19.

    Wen W, Chen WS, Xiao N, Bender R, Ghazalpour A, Tan Z, et al. Mutations in the kinase domain of the HER2/ERBB2 gene identified in a wide variety of human cancers. J Mol Diagn. 2015;17(5):487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25(3):282–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ, et al. NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res. 1998;58(22):5123–9.

  22. 22.

    Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99(8):628–38.

  23. 23.

    Molina MA, Saez R, Ramsey EE, Garcia-Barchino MJ, Rojo F, Evans AJ, et al. NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2002;8(2):347–53.

    CAS  Google Scholar 

  24. 24.

    Xia W, Liu Z, Zong R, Liu L, Zhao S, Bacus SS, et al. Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors. Mol Cancer Ther. 2011;10(8):1367–74.

  25. 25.

    Saez R, Molina MA, Ramsey EE, Rojo F, Keenan EJ, Albanell J, et al. p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res. 2006;12(2):424–31.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Sperinde J, Jin X, Banerjee J, Penuel E, Saha A, Diedrich G, et al. Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin Cancer Res: Off J Am Assoc Cancer Res. 2010;16(16):4226–35.

  27. 27.

    Duchnowska R, Sperinde J, Chenna A, Huang W, Weidler JM, Winslow J, et al. Quantitative HER2 and p95HER2 levels in primary breast cancers and matched brain metastases. Neuro-Oncology. 2015;17(9):1241–9.

  28. 28.

    Lin YZ, Clinton GM. A soluble protein related to the HER-2 proto-oncogene product is released from human breast carcinoma cells. Oncogene. 1991;6(4):639–43.

    CAS  PubMed  Google Scholar 

  29. 29.

    Pupa SM, Menard S, Morelli D, Pozzi B, De Palo G, Colnaghi MI. The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage. Oncogene. 1993;8(11):2917–23.

    CAS  PubMed  Google Scholar 

  30. 30.

    Yuan CX, Lasut AL, Wynn R, Neff NT, Hollis GF, Ramaker ML, et al. Purification of Her-2 extracellular domain and identification of its cleavage site. Protein Expr Purif. 2003;29(2):217–22.

  31. 31.

    Zabrecky JR, Lam T, McKenzie SJ, Carney W. The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. J Biol Chem. 1991;266(3):1716–20.

    CAS  PubMed  Google Scholar 

  32. 32.

    Kwong KY, Hung MC. A novel splice variant of HER2 with increased transformation activity. Mol Carcinog. 1998;23(2):62–8.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Anido J, Scaltriti M, Bech Serra JJ, Santiago Josefat B, Todo FR, Baselga J, et al. Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J. 2006;25(13):3234–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Scott GK, Robles R, Park JW, Montgomery PA, Daniel J, Holmes WE, et al. A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells. Mol Cell Biol. 1993;13(4):2247–57.

  35. 35.

    Pedersen K, Angelini PD, Laos S, Bach-Faig A, Cunningham MP, Ferrer-Ramon C, et al. A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis. Mol Cell Biol. 2009;29(12):3319–31.

  36. 36.

    Xia W, Liu LH, Ho P, Spector NL. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene. 2004;23(3):646–53.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Segatto O, King CR, Pierce JH, Di Fiore PP, Aaronson SA. Different structural alterations upregulate in vitro tyrosine kinase activity and transforming potency of the erbB-2 gene. Mol Cell Biol. 1988;8(12):5570–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Egeblad M, Mortensen OH, Jaattela M. Truncated ErbB2 receptor enhances ErbB1 signaling and induces reversible, ERK-independent loss of epithelial morphology. Int J Cancer. 2001;94(2):185–91.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Alajati A, Sausgruber N, Aceto N, Duss S, Sarret S, Voshol H, et al. Mammary tumor formation and metastasis evoked by a HER2 splice variant. Cancer Res. 2013;73(17):5320–7.

  40. 40.

    • Rafn B, Nielsen CF, Andersen SH, Szyniarowski P, Corcelle-Termeau E, Valo E, et al. ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression. Mol Cell. 2012;45(6):764–76. This paper is the first description of the involvement of lysosome in the invasion of human ErbB2-positive breast cancer cells.

  41. 41.

    Castiglioni F, Tagliabue E, Campiglio M, Pupa SM, Balsari A, Menard S. Role of exon-16-deleted HER2 in breast carcinomas. Endocr Relat Cancer. 2006;13(1):221–32.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Castagnoli L, Iezzi M, Ghedini GC, Ciravolo V, Marzano G, Lamolinara A, et al. Activated d16HER2 homodimers and SRC kinase mediate optimal efficacy for trastuzumab. Cancer Res. 2014;74(21):6248–59.

  43. 43.

    Turpin J, Ling C, Crosby EJ, Hartman ZC, Simond AM, Chodosh LA, et al. The ErbB2DeltaEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment. Oncogene. 2016;35(47):6053–64.

  44. 44.

    Nielsen DL, Kumler I, Palshof JA, Andersson M. Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Breast. 2013;22(1):1–12.

    Article  PubMed  Google Scholar 

  45. 45.

    Rocque G, Onitilo A, Engel J, Pettke E, Boshoven A, Kim K, et al. Adjuvant therapy for HER2+ breast cancer: practice, perception, and toxicity. Breast Cancer Res Treat. 2012;131(2):713–21.

  46. 46.

    Moasser MM. Targeting the function of the HER2 oncogene in human cancer therapeutics. Oncogene. 2007;26(46):6577–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Venur VA, Leone JP. Targeted therapies for brain metastases from breast cancer. Int J Mol Sci 2016;17(9).

  48. 48.

    Yuan P, Gao SL. Management of breast cancer brain metastases: focus on human epidermal growth factor receptor 2-positive breast cancer. Chronic Dis Transl Med. 2017;3(1):21–32.

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Palmieri D, Bronder JL, Herring JM, Yoneda T, Weil RJ, Stark AM, et al. Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res. 2007;67(9):4190–8.

  50. 50.

    Tural D, Akar E, Mutlu H, Kilickap S. P95 HER2 fragments and breast cancer outcome. Expert Rev Anticancer Ther. 2014;14(9):1089–96.

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Keith KC, Lee Y, Ewend MG, Zagar TM, Anders CK. Activity of trastuzumab-emtansine (Tdm1) in Her2-positive breast cancer brain metastases: a case series. Cancer Treat Commun. 2016;7:43–6.

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Gleeson JP, Keegan NM, Morris PG. Adding pertuzumab to trastuzumab and taxanes in HER2 positive breast cancer. Expert Opin Biol Ther 2017.

  53. 53.

    Mustacchi G, Biganzoli L, Pronzato P, Montemurro F, Dambrosio M, Minelli M, et al. HER2-positive metastatic breast cancer: a changing scenario. Crit Rev Oncol Hematol. 2015;95(1):78–87.

  54. 54.

    Kumler I, Tuxen MK, Nielsen DL. A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev 2013.

  55. 55.

    Blumenthal GM, Scher NS, Cortazar P, Chattopadhyay S, Tang S, Song P, et al. First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2013;19(18):4911–6.

  56. 56.

    Daemen A, Manning G. HER2 is not a cancer subtype but rather a pan-cancer event and is highly enriched in AR-driven breast tumors. Breast Cancer Res. 2018;20(1):8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Luque-Cabal M, Garcia-Teijido P, Fernandez-Perez Y, Sanchez-Lorenzo L, Palacio-Vazquez I. Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol. 2016;10(Suppl 1):21–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Tjensvoll K, Oltedal S, Heikkila R, Kvaloy JT, Gilje B, Reuben JM, et al. Persistent tumor cells in bone marrow of non-metastatic breast cancer patients after primary surgery are associated with inferior outcome. BMC Cancer. 2012;12:190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    McInnes LM, Jacobson N, Redfern A, Dowling A, Thompson EW, Saunders CM. Clinical implications of circulating tumor cells of breast cancer patients: role of epithelial-mesenchymal plasticity. Front Oncol. 2015;5:42.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Castle J, Shaker H, Morris K, Tugwood JD, Kirwan CC. The significance of circulating tumour cells in breast cancer: a review. Breast. 2014;23(5):552–60.

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    • Jordan NV, Bardia A, Wittner BS, Benes C, Ligorio M, Zheng Y, et al. HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature. 2016;537(7618):102–6. This paper establishes the interconvertion between the CTCs in breast cancer, where CTCs can change their ErbB2 status, which will affect their aggressiveness and treatment resistance.

  62. 62.

    Lodato RF, Maguire HC Jr, Greene MI, Weiner DB, LiVolsi VA. Immunohistochemical evaluation of c-erbB-2 oncogene expression in ductal carcinoma in situ and atypical ductal hyperplasia of the breast. Mod Pathol. 1990;3(4):449–54.

  63. 63.

    van de Vijver MJ, Peterse JL, Mooi WJ, Wisman P, Lomans J, Dalesio O, et al. Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med. 1988;319(19):1239–45.

  64. 64.

    Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK, et al. Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci U S A. 2004;101(5):1257–62.

  65. 65.

    Pradeep CR, Zeisel A, Kostler WJ, Lauriola M, Jacob-Hirsch J, Haibe-Kains B, et al. Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions. Oncogene. 2012;31(31):3569–83.

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL. Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. J Biol Chem. 2004;279(23):24505–13.

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Bertelsen V, Stang E. The mysterious ways of ErbB2/HER2 trafficking. Membranes (Basel). 2014;4(3):424–46.

    Article  CAS  Google Scholar 

  68. 68.

    Hommelgaard AM, Lerdrup M, van Deurs B. Association with membrane protrusions makes ErbB2 an internalization-resistant receptor. Mol Biol Cell. 2004;15(4):1557–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Castagnola P, Bellese G, Birocchi F, Gagliani MC, Tacchetti C, Cortese K. Identification of an HSP90 modulated multi-step process for ERBB2 degradation in breast cancer cells. Oncotarget. 2016;7(51):85411–29.

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Jeong J, VanHouten JN, Dann P, Kim W, Sullivan C, Yu H, et al. PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer. Proc Natl Acad Sci U S A. 2016;113(3):E282–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Jeong J, VanHouten JN, Kim W, Dann P, Sullivan C, Choi J, et al. The scaffolding protein NHERF1 regulates the stability and activity of the tyrosine kinase HER2. J Biol Chem. 2017;292(16):6555–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Tan M, Li P, Sun M, Yin G, Yu D. Upregulation and activation of PKC alpha by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKC alpha and Src inhibitors. Oncogene. 2006;25(23):3286–95.

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Bailey TA, Luan H, Tom E, Bielecki TA, Mohapatra B, Ahmad G, et al. A kinase inhibitor screen reveals protein kinase C-dependent endocytic recycling of ErbB2 in breast cancer cells. J Biol Chem. 2014;289(44):30443–58.

  74. 74.

    Magnifico A, Albano L, Campaner S, Campiglio M, Pilotti S, Menard S, et al. Protein kinase Calpha determines HER2 fate in breast carcinoma cells with HER2 protein overexpression without gene amplification. Cancer Res. 2007;67(11):5308–17.

  75. 75.

    Taylor MA, Lee YH, Schiemann WP. Role of TGF-beta and the tumor microenvironment during mammary tumorigenesis. Gene Expr. 2011;15(3):117–32.

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Chow A, Arteaga CL, Wang SE. When tumor suppressor TGFbeta meets the HER2 (ERBB2) oncogene. J Mammary Gland Biol Neoplasia. 2011;16(2):81–8.

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Wang SE, Xiang B, Zent R, Quaranta V, Pozzi A, Arteaga CL. Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton. Cancer Res. 2009;69(2):475–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Muraoka RS, Koh Y, Roebuck LR, Sanders ME, Brantley-Sieders D, Gorska AE, et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol. 2003;23(23):8691–703.

  79. 79.

    Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A. 2003;100(14):8430–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, et al. Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene. 2006;25(24):3408–23.

  81. 81.

    Bisaro B, Sciortino M, Colombo S, Camacho Leal MP, Costamagna A, Castellano I, et al. p130Cas scaffold protein regulates ErbB2 stability by altering breast cancer cell sensitivity to autophagy. Oncotarget. 2016;7(4):4442–53.

  82. 82.

    Tornillo G, Defilippi P, Cabodi S. Cas proteins: dodgy scaffolding in breast cancer. Breast Cancer Res : BCR. 2014;16(5):443.

    Article  CAS  PubMed  Google Scholar 

  83. 83.

    Chang J, Nicolau MM, Cox TR, Wetterskog D, Martens JW, Barker HE, et al. LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling. Breast Cancer Res : BCR. 2013;15(4):R67.

    Article  PubMed  Google Scholar 

  84. 84.

    Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF 3rd, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A. 2003;100(15):8933–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Berghoff AS, Bartsch R, Preusser M, Ricken G, Steger GG, Bago-Horvath Z, et al. Co-overexpression of HER2/HER3 is a predictor of impaired survival in breast cancer patients. Breast. 2014;23(5):637–43.

  86. 86.

    Vaught DB, Stanford JC, Young C, Hicks DJ, Wheeler F, Rinehart C, et al. HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res. 2012;72(10):2672–82.

  87. 87.

    Schulze WX, Deng L, Mann M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol. 2005;1:2005–0008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Dey N, Williams C, Leyland-Jones B, De P. A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK. Am J Transl Res. 2015;7(4):733–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Campbell AJ, Knight G, Walsh P, Bowen AC. Effective treatment of infant botulism on day 13 after symptom onset with human botulism antitoxin. J Paediatr Child Health. 2017;53(4):416–8.

    Article  PubMed  Google Scholar 

  90. 90.

    Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27(47):6120–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, Gasparini P, et al. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15(6):2010–21.

  92. 92.

    Lee CY, Lin Y, Bratman SV, Feng W, Kuo AH, Scheeren FA, et al. Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation. Cancer Res. 2014;74(1):341–52.

    Article  CAS  PubMed  Google Scholar 

  93. 93.

    Bulfoni M, Turetta M, Del Ben F, Di Loreto C, Beltrami AP, Cesselli D. Dissecting the heterogeneity of circulating tumor cells in metastatic breast cancer: going far beyond the needle in the haystack. Int J Mol Sci 2016;17(10).

  94. 94.

    Giordano A, Gao H, Anfossi S, Cohen E, Mego M, Lee BN, et al. Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol Cancer Ther. 2012;11(11):2526–34.

  95. 95.

    Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V, Auvinen P, et al. Transcription factors zeb1, twist and snai1 in breast carcinoma. BMC Cancer. 2011;11:73.

  96. 96.

    Al Saleh S, Sharaf LH, Luqmani YA. Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (review). Int J Oncol. 2011;38(5):1197–217.

    PubMed  Google Scholar 

  97. 97.

    Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20(5):576–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Moyret-Lalle C, Ruiz E, Puisieux A. Epithelial-mesenchymal transition transcription factors and miRNAs: “plastic surgeons” of breast cancer. World J Clin Oncol. 2014;5(3):311–22.

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Roxanis I. Occurrence and significance of epithelial-mesenchymal transition in breast cancer. J Clin Pathol. 2013;66(6):517–21.

    Article  CAS  PubMed  Google Scholar 

  100. 100.

    Friedl P, Locker J, Sahai E, Segall JE. Classifying collective cancer cell invasion. Nat Cell Biol. 2012;14(8):777–83.

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Bastid J. EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. Cancer Metastasis Rev. 2012;31(1–2):277–83.

    Article  PubMed  Google Scholar 

  102. 102.

    Zu X, Zhang Q, Cao R, Liu J, Zhong J, Wen G, et al. Transforming growth factor-beta signaling in tumor initiation, progression and therapy in breast cancer: an update. Cell Tissue Res. 2012;347(1):73–84.

  103. 103.

    Lu J, Guo H, Treekitkarnmongkol W, Li P, Zhang J, Shi B, et al. 14-3-3zeta cooperates with ErbB2 to promote ductal carcinoma in situ progression to invasive breast cancer by inducing epithelial-mesenchymal transition. Cancer Cell. 2009;16(3):195–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37.

    Article  CAS  PubMed  Google Scholar 

  105. 105.

    Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16(6):488–94.

    Article  CAS  PubMed  Google Scholar 

  106. 106.

    Wu Y, Shang X, Sarkissyan M, Slamon D, Vadgama JV. FOXO1A is a target for HER2-overexpressing breast tumors. Cancer Res. 2010;70(13):5475–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Kambach DM, Sodi VL, Lelkes PI, Azizkhan-Clifford J, Reginato MJ. ErbB2, FoxM1 and 14-3-3zeta prime breast cancer cells for invasion in response to ionizing radiation. Oncogene. 2014;33(5):589–98.

    Article  CAS  PubMed  Google Scholar 

  108. 108.

    Garg M. Epithelial-mesenchymal transition—activating transcription factors—multifunctional regulators in cancer. World J Stem Cells. 2013;5(4):188–95.

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    He Y, Northey JJ, Pelletier A, Kos Z, Meunier L, Haibe-Kains B, et al. The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer. Oncogene. 2017;36(24):3490–503.

  110. 110.

    Gilkes DM. Implications of hypoxia in breast cancer metastasis to bone. Int J Mol Sci. 2016;17(10)

  111. 111.

    Whelan KA, Schwab LP, Karakashev SV, Franchetti L, Johannes GJ, Seagroves TN, et al. The oncogene HER2/neu (ERBB2) requires the hypoxia-inducible factor HIF-1 for mammary tumor growth and anoikis resistance. J Biol Chem. 2013;288(22):15865–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Romagnoli M, Belguise K, Yu Z, Wang X, Landesman-Bollag E, Seldin DC, et al. Epithelial-to-mesenchymal transition induced by TGF-beta1 is mediated by Blimp-1-dependent repression of BMP-5. Cancer Res. 2012;72(23):6268–78.

  113. 113.

    Sciortino M, Camacho-Leal MDP, Orso F, Grassi E, Costamagna A, Provero P, et al. Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion. Sci Rep. 2017;7(1):1145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Donadelli M, Dando I, Fiorini C, Palmieri M. Regulation of miR-23b expression and its dual role on ROS production and tumour development. Cancer Lett. 2014;349(2):107–13.

    Article  CAS  PubMed  Google Scholar 

  115. 115.

    Pellegrino L, Stebbing J, Braga VM, Frampton AE, Jacob J, Buluwela L, et al. miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts. Nucleic Acids Res. 2013;41(10):5400–12.

  116. 116.

    Yue CH, Chiu YW, Tung JN, Tzang BS, Shiu JJ, Huang WH, et al. Expression of protein kinase C alpha and the MZF-1 and Elk-1 transcription factors in human breast cancer cells. Chin J Physiol. 2012;55(1):31–6.

  117. 117.

    Tvingsholm SA, Hansen MB, Clemmensen KKB, Brix DM, Rafn B, Frankel LB, et al. Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1. Oncogene. 2018;7(2):14.

    Article  CAS  Google Scholar 

  118. 118.

    Mudduluru G, Vajkoczy P, Allgayer H. Myeloid zinc finger 1 induces migration, invasion, and in vivo metastasis through Axl gene expression in solid cancer. Mol Cancer Res. 2010;8(2):159–69.

    Article  CAS  PubMed  Google Scholar 

  119. 119.

    Tsai LH, Wu JY, Cheng YW, Chen CY, Sheu GT, Wu TC, et al. The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss. Oncogene. 2015;34(13):1641–9.

  120. 120.

    Giunciuglio D, Culty M, Fassina G, Masiello L, Melchiori A, Paglialunga G, et al. Invasive phenotype of MCF10A cells overexpressing c-Ha-ras and c-erbB-2 oncogenes. Int J Cancer. 1995;63(6):815–22.

  121. 121.

    Connolly J, Rose D. Expression of the invasive phenotype by MCF-7 human breast cancer cells transfected to overexpress protein kinase C-alpha or the erbB2 proto-oncogene. Int J Oncol. 1997;10(1):71–6.

    CAS  PubMed  Google Scholar 

  122. 122.

    Watabe T, Yoshida K, Shindoh M, Kaya M, Fujikawa K, Sato H, et al. The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. Int J Cancer. 1998;77(1):128–37.

  123. 123.

    Kim S, Han J, Shin I, Kil WH, Lee JE, Nam SJ. A functional comparison between the HER2(high)/HER3 and the HER2(low)/HER3 dimers on heregulin-beta1-induced MMP-1 and MMP-9 expression in breast cancer cells. Exp Mol Med. 2012;44(8):473–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Park YH, Jung HH, Ahn JS, Im YH. Ets-1 upregulates HER2-induced MMP-1 expression in breast cancer cells. Biochem Biophys Res Commun. 2008;377(2):389–94.

    Article  CAS  PubMed  Google Scholar 

  125. 125.

    Rath MG, Masciari S, Gelman R, Miron A, Miron P, Foley K, et al. Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat. 2013;139(1):193–8.

  126. 126.

    Yallowitz AR, Li D, Lobko A, Mott D, Nemajerova A, Marchenko N. Mutant p53 amplifies epidermal growth factor receptor family signaling to promote mammary tumorigenesis. Mol Cancer Res. 2015;13(4):743–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Li D, Marchenko ND. ErbB2 inhibition by lapatinib promotes degradation of mutant p53 protein in cancer cells. Oncotarget. 2017;8(4):5823–33.

    PubMed  Google Scholar 

  128. 128.

    Feldner JC, Brandt BH. Cancer cell motility—on the road from c-erbB-2 receptor steered signaling to actin reorganization. Exp Cell Res. 2002;272(2):93–108.

    Article  CAS  PubMed  Google Scholar 

  129. 129.

    Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA. Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol. 1997;137(2):481–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Garcia-Castillo J, Pedersen K, Angelini PD, Bech-Serra JJ, Colome N, Cunningham MP, et al. HER2 carboxyl-terminal fragments regulate cell migration and cortactin phosphorylation. J Biol Chem. 2009;284(37):25302–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Eswaran J, Soundararajan M, Kumar R, Knapp S. UnPAKing the class differences among p21-activated kinases. Trends Biochem Sci. 2008;33(8):394–403.

    Article  CAS  PubMed  Google Scholar 

  132. 132.

    Whale A, Hashim FN, Fram S, Jones GE, Wells CM. Signalling to cancer cell invasion through PAK family kinases. Front Biosci (Landmark Ed). 2011;16:849–64.

    Article  CAS  Google Scholar 

  133. 133.

    Arias-Romero LE, Villamar-Cruz O, Pacheco A, Kosoff R, Huang M, Muthuswamy SK, et al. A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells. Oncogene. 2010;29(43):5839–49.

  134. 134.

    Liu Y, Chen N, Cui X, Zheng X, Deng L, Price S, et al. The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis. Oncogene. 2010;29(44):5883–94.

  135. 135.

    Rafn B, Kallunki T. A way to invade: a story of ErbB2 and lysosomes. Cell Cycle. 2012;11(13):2415–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Brix DM, Rafn B, Bundgaard Clemmensen K, Andersen SH, Ambartsumian N, Jaattela M, et al. Screening and identification of small molecule inhibitors of ErbB2-induced invasion. Mol Oncol. 2014;8(8):1703–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Kallunki T, Olsen OD, Jaattela M. Cancer-associated lysosomal changes: friends or foes? Oncogene. 2013;32(16):1995–2004.

    Article  CAS  PubMed  Google Scholar 

  138. 138.

    Mason SD, Joyce JA. Proteolytic networks in cancer. Trends Cell Biol. 2011;21(4):228–37.

    Article  CAS  PubMed  Google Scholar 

  139. 139.

    Hamalisto S, Jaattela M. Lysosomes in cancer-living on the edge (of the cell). Curr Opin Cell Biol. 2016;39:69–76.

    Article  CAS  PubMed  Google Scholar 

  140. 140.

    Fehrenbacher N, Bastholm L, Kirkegaard-Sorensen T, Rafn B, Bottzauw T, Nielsen C, et al. Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2. Cancer Res. 2008;68(16):6623–33.

  141. 141.

    Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G, Spampanato C, et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011;21(3):421–30.

  142. 142.

    Jaiswal JK, Lauritzen SP, Scheffer L, Sakaguchi M, Bunkenborg J, Simon SM, et al. S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat Commun. 2014;5:3795.

  143. 143.

    Lauritzen G, Jensen MB, Boedtkjer E, Dybboe R, Aalkjaer C, Nylandsted J, et al. NBCn1 and NHE1 expression and activity in DeltaNErbB2 receptor-expressing MCF-7 breast cancer cells: contributions to pHi regulation and chemotherapy resistance. Exp Cell Res. 2010;316(15):2538–53.

    Article  CAS  PubMed  Google Scholar 

  144. 144.

    Gorbatenko A, Olesen CW, Morup N, Thiel G, Kallunki T, Valen E, et al. ErbB2 upregulates the Na+,HCO3—cotransporter NBCn1/SLC4A7 in human breast cancer cells via Akt, ERK, Src, and Kruppel-like factor 4. FASEB J. 2013.

  145. 145.

    Brisson L, Reshkin SJ, Gore J, Roger S. pH regulators in invadosomal functioning: proton delivery for matrix tasting. Eur J Cell Biol. 2012;91(11–12):847–60.

    Article  CAS  PubMed  Google Scholar 

  146. 146.

    Chevalier C, Collin G, Descamps S, Touaitahuata H, Simon V, Reymond N, et al. TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion. Nat Commun. 2016;7:10765.

  147. 147.

    Franco M, Furstoss O, Simon V, Benistant C, Hong WJ, Roche S. The adaptor protein Tom1L1 is a negative regulator of Src mitogenic signaling induced by growth factors. Mol Cell Biol. 2006;26(5):1932–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Tang J, Ahmad A, Sarkar FH. The role of microRNAs in breast cancer migration, invasion and metastasis. Int J Mol Sci. 2012;13(10):13414–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Muller V, Gade S, Steinbach B, Loibl S, von Minckwitz G, Untch M, et al. Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. Breast Cancer Res Treat. 2014;147(1):61–8.

    Article  CAS  PubMed  Google Scholar 

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Funding

The work at the laboratory of TK is supported by the Danish Cancer Society Scientific Committee (KBVU) (R124-A7854-15-S2 and R56-A3108-12-S2), the Danish National Research Foundation (DNRF125), the Novo Nordisk Foundation (NNF15OC0017324), and the Danish Medical Research Council (0602-02386B).

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Correspondence to Tuula Kallunki.

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This article is part of the Topical Collection on Kinase Inhibitor

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Tvingsholm, S.A., Brix, D.M. & Kallunki, T. Molecular and Transcriptional Signatures for ErbB2-Induced Invasion. Curr Pharmacol Rep 5, 43–55 (2019). https://doi.org/10.1007/s40495-018-0146-1

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Keywords

  • EMT
  • HER2
  • Invasion
  • Lysosome
  • Metastasis
  • MZF1