Top

Journal of Mammary Gland Biology and Neoplasia

Published in:

01-12-2014

The HER2 Signaling Network in Breast Cancer—Like a Spider in its Web

Authors: A. Dittrich, H. Gautrey, D. Browell, A. Tyson-Capper

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 3-4/2014

Abstract

The human epidermal growth factor receptor 2 (HER2) is a major player in the survival and proliferation of tumour cells and is overexpressed in up to 30 % of breast cancer cases. A considerable amount of work has been undertaken to unravel the activity and function of HER2 to try and develop effective therapies that impede its action in HER2 positive breast tumours. Research has focused on exploring the HER2 activated phosphoinositide-3-kinase (PI3K)/AKT and rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathways for therapies. Despite the advances, cases of drug resistance and recurrence of disease still remain a challenge to overcome. An important aspect for drug resistance is the complexity of the HER2 signaling network. This includes the crosstalk between HER2 and hormone receptors; its function as a transcription factor; the regulation of HER2 by protein-tyrosine phosphatases and a complex network of positive and negative feedback-loops. This review summarises the current knowledge of many different HER2 interactions to illustrate the complexity of the HER2 network from the transcription of HER2 to the effect of its downstream targets. Exploring the novel avenues of the HER2 signaling could yield a better understanding of treatment resistance and give rise to developing new and more effective therapies.

Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. J Control Release. 2010;146(3):264–75. doi:10.1016/j.jconrel.2010.04.009.PubMedCentralPubMed

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–82.PubMed

Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12.PubMed

Hurvitz SA, Hu Y, O’Brien N, Finn RS. Current approaches and future directions in the treatment of HER2-positive breast cancer. Cancer Treat Rev. 2013;39(3):219–29. doi:10.1016/j.ctrv.2012.04.008.PubMed

Schulz R, Streller F, Scheel AH, Ruschoff J, Reinert MC, Dobbelstein M, et al. HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. Cell Death Dis. 2014;5:e980. doi:10.1038/cddis.2013.508.PubMedCentralPubMed

Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. doi:10.1038/35052073.PubMed

Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI. Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys. 2004;58(2):344–52.PubMed

Kufe DW. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene. 2013;32(9):1073–81. doi:10.1038/onc.2012.158.PubMedCentralPubMed

Eisenberg A, Biener E, Charlier M, Krishnan RV, Djiane J, Herman B, et al. Transactivation of erbB2 by short and long isoforms of leptin receptors. FEBS Lett. 2004;565(1–3):139–42. doi:10.1016/j.febslet.2004.03.089.PubMed

10.

De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signaling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 2012;16 Suppl 2:S17–27. doi:10.1517/14728222.2011.639361.PubMed

11.

Giuliano M, Trivedi MV, Schiff R. Bidirectional crosstalk between the estrogen receptor and human epidermal growth factor receptor 2 signaling pathways in breast cancer: molecular basis and clinical implications. Breast Care. 2013;8(4):256–62. doi:10.1159/000354253.PubMedCentralPubMed

12.

Grabinski N, Mollmann K, Milde-Langosch K, Muller V, Schumacher U, Brandt B, et al. AKT3 regulates ErbB2, ErbB3 and estrogen receptor alpha expression and contributes to endocrine therapy resistance of ErbB2 breast tumor cells from Balb-neuT mice. Cell Signal. 2014. doi:10.1016/j.cellsig.2014.01.018.

13.

Lattrich C, Stegerer A, Haring J, Schuler S, Ortmann O, Treeck O. Estrogen receptor beta agonists affect growth and gene expression of human breast cancer cell lines. Steroids. 2013;78(2):195–202. doi:10.1016/j.steroids.2012.10.014.PubMed

14.

Chia KM, Liu J, Francis GD, Naderi A. A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia. 2011;13(2):154–66.PubMedCentralPubMed

15.

Naderi A, Hughes-Davies L. A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. Neoplasia. 2008;10(6):542–8.PubMedCentralPubMed

16.

Beguelin W, Diaz Flaque MC, Proietti CJ, Cayrol F, Rivas MA, Tkach M, et al. Progesterone receptor induces ErbB-2 nuclear translocation to promote breast cancer growth via a novel transcriptional effect: ErbB-2 function as a coactivator of Stat3. Mol Cell Biol. 2010;30(23):5456–72. doi:10.1128/MCB. 00012-10.PubMedCentralPubMed

17.

Dillon MF, Stafford AT, Kelly G, Redmond AM, McIlroy M, Crotty TB, et al. Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients. Endocrinol Relat Cancer. 2008;15(3):745–53. doi:10.1677/ERC-08-0009.

18.

Vernimmen D, Begon D, Salvador C, Gofflot S, Grooteclaes M, Winkler R. Identification of HTF (HER2 transcription factor) as an AP-2 (activator protein-2) transcription factor and contribution of the HTF binding site to ERBB2 gene overexpression. Biochem J. 2003;370(Pt 1):323–9. doi:10.1042/BJ20021238.PubMedCentralPubMed

19.

Vernimmen D, Gueders M, Pisvin S, Delvenne P, Winkler R. Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers. Br J Cancer. 2003;89(5):899–906. doi:10.1038/sj.bjc.6601200.PubMedCentralPubMed

20.

Dillon RL, Brown ST, Ling C, Shioda T, Muller WJ. An EGR2/CITED1 transcription factor complex and the 14-3-3sigma tumor suppressor are involved in regulating ErbB2 expression in a transgenic-mouse model of human breast cancer. Mol Cell Biol. 2007;27(24):8648–57. doi:10.1128/MCB. 00866-07.PubMedCentralPubMed

21.

Qian L, Chen L, Shi M, Yu M, Jin B, Hu M, et al. A novel cis-acting element in Her2 promoter regulated by Stat3 in mammary cancer cells. Biochem Biophys Res Commun. 2006;345(2):660–8. doi:10.1016/j.bbrc.2006.04.153.PubMed

22.

Contino F, Mazzarella C, Ferro A, Lo Presti M, Roz E, Lupo C, et al. Negative transcriptional control of ERBB2 gene by MBP-1 and HDAC1: diagnostic implications in breast cancer. BMC Cancer. 2013;13:81. doi:10.1186/1471-2407-13-81.PubMedCentralPubMed

23.

Lo Presti M, Ferro A, Contino F, Mazzarella C, Sbacchi S, Roz E, et al. Myc promoter-binding protein-1 (MBP-1) is a novel potential prognostic marker in invasive ductal breast carcinoma. PLoS One. 2010;5(9):e12961. doi:10.1371/journal.pone.0012961.PubMedCentralPubMed

24.

Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell. 2007;129(7):1275–86. doi:10.1016/j.cell.2007.04.034.PubMedCentralPubMed

25.

Jackson C, Browell D, Gautrey H, Tyson-Capper A. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance. Int J Cell Biol. 2013;2013:973584. doi:10.1155/2013/973584.PubMedCentralPubMed

26.

Sasso M, Bianchi F, Ciravolo V, Tagliabue E, Campiglio M. HER2 splice variants and their relevance in breast cancer. J Nucleic Acids Investig. 2011;2(1). doi:10.4081/jnai.2011.e9.

27.

Aigner A, Juhl H, Malerczyk C, Tkybusch A, Benz CC, Czubayko F. Expression of a truncated 100 kDa HER2 splice variant acts as an endogenous inhibitor of tumour cell proliferation. Oncogene. 2001;20(17):2101–11. doi:10.1038/sj.onc.1204305.PubMed

28.

Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci U S A. 1999;96(19):10869–74.PubMedCentralPubMed

29.

Hu P, Feng J, Zhou T, Wang J, Jing B, Yu M, et al. In vivo identification of the interaction site of ErbB2 extracellular domain with its autoinhibitor. J Cell Physiol. 2005;205(3):335–43. doi:10.1002/jcp.20409.PubMed

30.

Marchini C, Gabrielli F, Iezzi M, Zenobi S, Montani M, Pietrella L, et al. The human splice variant Delta16HER2 induces rapid tumor onset in a reporter transgenic mouse. PLoS One. 2011;6(4):e18727. doi:10.1371/journal.pone.0018727.PubMedCentralPubMed

31.

Mitra D, Brumlik MJ, Okamgba SU, Zhu Y, Duplessis TT, Parvani JG, et al. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol Cancer Ther. 2009;8(8):2152–62. doi:10.1158/1535-7163.MCT-09-0295.PubMed

32.

Castiglioni F, Tagliabue E, Campiglio M, Pupa SM, Balsari A, Menard S. Role of exon-16-deleted HER2 in breast carcinomas. Endocrinol Relat Cancer. 2006;13(1):221–32. doi:10.1677/erc.1.01047.

33.

Scott GK, Marx C, Berger CE, Saunders LR, Verdin E, Schafer S, et al. Destabilization of ERBB2 transcripts by targeting 3′ untranslated region messenger RNA associated HuR and histone deacetylase-6. Mol Cancer Res: MCR. 2008;6(7):1250–8. doi:10.1158/1541-7786.MCR-07-2110.PubMedCentralPubMed

34.

Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem. 2007;282(2):1479–86. doi:10.1074/jbc.M609383200.PubMed

35.

Ferracin M, Bassi C, Pedriali M, Pagotto S, D’Abundo L, Zagatti B, et al. miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. Mol Cancer. 2013;12(1):130. doi:10.1186/1476-4598-12-130.PubMedCentralPubMed

36.

Chen H, Sun JG, Cao XW, Ma XG, Xu JP, Luo FK, et al. Preliminary validation of ERBB2 expression regulated by miR-548d-3p and miR-559. Biochem Biophys Res Commun. 2009;385(4):596–600. doi:10.1016/j.bbrc.2009.05.113.PubMed

37.

Epis MR, Giles KM, Barker A, Kendrick TS, Leedman PJ. miR-331-3p regulates ERBB-2 expression and androgen receptor signaling in prostate cancer. J Biol Chem. 2009;284(37):24696–704. doi:10.1074/jbc.M109.030098.PubMedCentralPubMed

38.

Pedersen K, Angelini P, Laos S, Bach-Faig A, Cunningham MP, Ferrer-Ramo’n C, et al. A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis. Mol Cell Biol. 2009;29(12):3319–31. doi:10.1128/MCB.01803-08.PubMedCentralPubMed

39.

Ward TM, Iorns E, Liu X, Hoe N, Kim P, Singh S, et al. Truncated p110 ERBB2 induces mammary epithelial cell migration, invasion and orthotopic xenograft formation, and is associated with loss of phosphorylated STAT5. Oncogene. 2013;32(19):2463–74. doi:10.1038/onc.2012.256.PubMedCentralPubMed

40.

Chandarlapaty S, Scaltriti M, Angelini P, Ye Q, Guzman M, Hudis CA, et al. Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth. Oncogene. 2010;29(3):325–34. doi:10.1038/onc.2009.337.PubMedCentralPubMed

41.

Tse C, Gauchez AS, Jacot W, Lamy PJ. HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer. Cancer Treat Rev. 2012;38(2):133–42. doi:10.1016/j.ctrv.2011.03.008.PubMed

42.

Xu W, Marcu M, Yuan X, Mimnaugh E, Patterson C, Neckers L. Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci U S A. 2002;99(20):12847–52. doi:10.1073/pnas.202365899.PubMedCentralPubMed

43.

Paris L, Cecchetti S, Spadaro F, Abalsamo L, Lugini L, Pisanu ME, et al. Inhibition of phosphatidylcholine-specific phospholipase C downregulates HER2 overexpression on plasma membrane of breast cancer cells. Breast Cancer Res. 2010;12(3):R27. doi:10.1186/bcr2575.PubMedCentralPubMed

44.

Barros FF, Powe DG, Ellis IO, Green AR. Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatments. Histopathology. 2010;56(5):560–72. doi:10.1111/j.1365-2559.2010.03494.x.PubMed

45.

Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, et al. Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie. 2008;90(2):369–79. doi:10.1016/j.biochi.2007.08.008.PubMed

46.

Dang M, Armbruster N, Miller MA, Cermeno E, Hartmann M, Bell GW, et al. Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways. Proc Natl Acad Sci U S A. 2013;110(24):9776–81. doi:10.1073/pnas.1307478110.PubMedCentralPubMed

47.

Daly JM, Olayioye MA, Wong AM, Neve R, Lane HA, Maurer FG, et al. NDF/heregulin-induced cell cycle changes and apoptosis in breast tumour cells: role of PI3 kinase and p38 MAP kinase pathways. Oncogene. 1999;18(23):3440–51. doi:10.1038/sj.onc.1202700.PubMed

48.

Pinkas-Kramarski R, Lenferink AE, Bacus SS, Lyass L, van de Poll ML, Klapper LN, et al. The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin. Oncogene. 1998;16(10):1249–58. doi:10.1038/sj.onc.1201642.PubMed

49.

Yang L, Li Y, Zhang Y. Identification of prolidase as a high affinity ligand of the ErbB2 receptor and its regulation of ErbB2 signaling and cell growth. Cell Death Dis. 2014;5:e1211. doi:10.1038/cddis.2014.187.PubMedCentralPubMed

50.

Long W, Yi P, Amazit L, LaMarca HL, Ashcroft F, Kumar R, et al. SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration. Mol Cell. 2010;37(3):321–32. doi:10.1016/j.molcel.2010.01.004.PubMedCentralPubMed

51.

Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, et al. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol. 2000;2(5):249–56. doi:10.1038/35010517.PubMed

52.

Rea K, Sensi M, Anichini A, Canevari S, Tomassetti A. EGFR/MEK/ERK/CDK5-dependent integrin-independent FAK phosphorylated on serine 732 contributes to microtubule depolymerization and mitosis in tumor cells. Cell Death Dis. 2013;4:e815. doi:10.1038/cddis.2013.353.PubMedCentralPubMed

53.

Pontillo CA, Garcia MA, Pena D, Cocca C, Chiappini F, Alvarez L, et al. Activation of c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration by hexachlorobenzene in MDA-MB-231 human breast cancer cell line. Toxicol Sci Off J Soc Toxicol. 2011;120(2):284–96. doi:10.1093/toxsci/kfq390.

54.

Balz LM, Bartkowiak K, Andreas A, Pantel K, Niggemann B, Zanker KS, et al. The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-gamma1 signaling in breast cancer cell migration and dissemination. J Pathol. 2012;227(2):234–44. doi:10.1002/path.3991.PubMed

55.

Hartman Z, Zhao H, Agazie YM. HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling. Oncogene. 2013;32(35):4169–80. doi:10.1038/onc.2012.418.PubMedCentralPubMed

56.

Soma D, Kitayama J, Yamashita H, Miyato H, Ishikawa M, Nagawa H. Leptin augments proliferation of breast cancer cells via transactivation of HER2. J Surg Res. 2008;149(1):9–14. doi:10.1016/j.jss.2007.10.012.PubMed

57.

Fiorio E, Mercanti A, Terrasi M, Micciolo R, Remo A, Auriemma A, et al. Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis. BMC Cancer. 2008;8:305. doi:10.1186/1471-2407-8-305.PubMedCentralPubMed

58.

Torres MP, Chakraborty S, Souchek J, Batra SK. Mucin-based targeted pancreatic cancer therapy. Curr Pharm Des. 2012;18(17):2472–81.PubMedCentralPubMed

59.

Mukhopadhyay P, Chakraborty S, Ponnusamy MP, Lakshmanan I, Jain M, Batra SK. Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy. Biochim Biophys Acta. 2011;1815(2):224–40. doi:10.1016/j.bbcan.2011.01.001.PubMedCentralPubMed

60.

Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, et al. Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein. Mol Cancer Res: MCR. 2003;1(10):765–75.PubMed

61.

Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003;2(6):702–6.PubMed

62.

Gangopadhyay S, Nandy A, Hor P, Mukhopadhyay A. Breast cancer stem cells: a novel therapeutic target. Clin Breast Cancer. 2013;13(1):7–15. doi:10.1016/j.clbc.2012.09.017.PubMed

63.

Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15(2):117–34. doi:10.1007/s10911-010-9178-9.PubMedCentralPubMed

64.

Hanse EA, Mashek DG, Becker JR, Solmonson AD, Mullany LK, Mashek MT, et al. Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4alpha. Cell Cycle. 2012;11(14):2681–90. doi:10.4161/cc.21019.PubMedCentralPubMed

65.

Roskoski Jr R. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2013;79C:34–74. doi:10.1016/j.phrs.2013.11.002.

66.

Imami K, Sugiyama N, Imamura H, Wakabayashi M, Tomita M, Taniguchi M, et al. Temporal profiling of lapatinib-suppressed phosphorylation signals in EGFR/HER2 pathways. Mol Cell Proteomics: MCP. 2012;11(12):1741–57. doi:10.1074/mcp.M112.019919.PubMedCentralPubMed

67.

Castaneda CA, Cortes-Funes H, Gomez HL, Ciruelos EM. The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. Cancer Metastasis Rev. 2010;29(4):751–9. doi:10.1007/s10555-010-9261-0.PubMed

68.

Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13(2):140–56. doi:10.1038/nrd4204.PubMedCentralPubMed

69.

Aksamitiene E, Kiyatkin A, Kholodenko BN. Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans. 2012;40(1):139–46. doi:10.1042/BST20110609.PubMed

70.

Yordy JS, Muise-Helmericks RC. Signal transduction and the Ets family of transcription factors. Oncogene. 2000;19(55):6503–13. doi:10.1038/sj.onc.1204036.PubMed

71.

Sistonen L, Holtta E, Lehvaslaiho H, Lehtola L, Alitalo K. Activation of the neu tyrosine kinase induces the fos/jun transcription factor complex, the glucose transporter and ornithine decarboxylase. J Cell Biol. 1989;109(5):1911–9.PubMed

72.

Chrestensen CA, Shuman JK, Eschenroeder A, Worthington M, Gram H, Sturgill TW. MNK1 and MNK2 regulation in HER2-overexpressing breast cancer lines. J Biol Chem. 2007;282(7):4243–52. doi:10.1074/jbc.M607368200.PubMed

73.

Chen RH, Sarnecki C, Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992;12(3):915–27.PubMedCentralPubMed

74.

Romeo Y, Zhang X, Roux PP. Regulation and function of the RSK family of protein kinases. Biochem J. 2012;441(2):553–69. doi:10.1042/BJ20110289.PubMed

75.

Kasza A. Signal-dependent Elk-1 target genes involved in transcript processing and cell migration. Biochim Biophys Acta. 2013;1829(10):1026–33. doi:10.1016/j.bbagrm.2013.05.004.PubMed

76.

Ueki K, Matsuda S, Tobe K, Gotoh Y, Tamemoto H, Yachi M, et al. Feedback regulation of mitogen-activated protein kinase kinase kinase activity of c-Raf-1 by insulin and phorbol ester stimulation. J Biol Chem. 1994;269(22):15756–61.PubMed

77.

Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34. doi:10.1016/j.cell.2010.06.011.PubMedCentralPubMed

78.

Dimova DK, Dyson NJ. The E2F transcriptional network: old acquaintances with new faces. Oncogene. 2005;24(17):2810–26. doi:10.1038/sj.onc.1208612.PubMed

79.

Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature. 1997;387(6631):422–6. doi:10.1038/387422a0.PubMed

80.

Wu L, de Bruin A, Wang H, Simmons T, Cleghorn W, Goldenberg LE, et al. Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis. Oncogene. 2013. doi:10.1038/onc.2013.511.

81.

Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, et al. The E2F1-3 transcription factors are essential for cellular proliferation. Nature. 2001;414(6862):457–62. doi:10.1038/35106593.PubMed

82.

Sharma N, Timmers C, Trikha P, Saavedra HI, Obery A, Leone G. Control of the p53-p21CIP1 Axis by E2f1, E2f2, and E2f3 is essential for G1/S progression and cellular transformation. J Biol Chem. 2006;281(47):36124–31. doi:10.1074/jbc.M604152200.PubMed

83.

Burris 3rd HA. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71(4):829–42. doi:10.1007/s00280-012-2043-3.PubMed

84.

Carpenter CL, Auger KR, Chanudhuri M, Yoakim M, Schaffhausen B, Shoelson S, et al. Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem. 1993;268(13):9478–83.PubMed

85.

Hopkins BD, Hodakoski C, Barrows D, Mense SM, Parsons RE. PTEN function: the long and the short of it. Trends Biochem Sci. 2014. doi:10.1016/j.tibs.2014.02.006.PubMedCentralPubMed

86.

Cohen Jr MM. The AKT genes and their roles in various disorders. Am J Med Genet A. 2013;161A(12):2931–7. doi:10.1002/ajmg.a.36101.PubMed

87.

Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91(2):231–41.PubMed

88.

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96(6):857–68.PubMed

89.

Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signaling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204. doi:10.1016/j.ctrv.2003.07.007.PubMed

90.

Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A. 2001;98(20):11598–603. doi:10.1073/pnas.181181198.PubMedCentralPubMed

91.

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. doi:10.1158/0008-5472.CAN-10-0176.PubMedCentralPubMed

92.

Wu Y, Elshimali Y, Sarkissyan M, Mohamed H, Clayton S, Vadgama JV. Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer. Am J Cancer Res. 2012;2(1):104–15.PubMedCentralPubMed

93.

Lazrek Y, Dubreuil O, Garambois V, Gaborit N, Larbouret C, Le Clorennec C, et al. Anti-HER3 domain 1 and 3 antibodies reduce tumor growth by hindering HER2/HER3 dimerization and AKT-induced MDM2, XIAP, and FoxO1 phosphorylation. Neoplasia. 2013;15(3):335–47.PubMedCentralPubMed

94.

Chakrabarty A, Bhola NE, Sutton C, Ghosh R, Kuba MG, Dave B, et al. Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. Cancer Res. 2013;73(3):1190–200. doi:10.1158/0008-5472.CAN-12-2440.PubMedCentralPubMed

95.

Ju JH, Yang W, Oh S, Nam K, Lee KM, Noh DY, et al. HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage. Biochem J. 2013;451(1):123–34. doi:10.1042/BJ20121716.PubMed

96.

Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol. 2002;4(9):648–57. doi:10.1038/ncb839.PubMed

97.

Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2010;30(4):908–21. doi:10.1128/MCB. 00601-09.PubMedCentralPubMed

98.

Proud CG. mTORC1 signaling and mRNA translation. Biochem Soc Trans. 2009;37(Pt 1):227–31. doi:10.1042/BST0370227.PubMed

99.

Sridharan S, Basu A. S6 kinase 2 promotes breast cancer cell survival via Akt. Cancer Res. 2011;71(7):2590–9. doi:10.1158/0008-5472.CAN-10-3253.PubMedCentralPubMed

100.

Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A. Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol. 2009;156(6):885–98. doi:10.1111/j.1476-5381.2008.00085.x.PubMedCentralPubMed

101.

Carpenter RL, Paw I, Dewhirst MW, Lo HW. Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells. Oncogene. 2014. doi:10.1038/onc.2013.582.PubMed

102.

Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28(1–2):15–33. doi:10.1007/s10555-008-9169-0.PubMed

103.

Ciocca DR, Arrigo AP, Calderwood SK. Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol. 2013;87(1):19–48. doi:10.1007/s00204-012-0918-z.PubMedCentralPubMed

104.

Khaleque MA, Bharti A, Sawyer D, Gong J, Benjamin IJ, Stevenson MA, et al. Induction of heat shock proteins by heregulin beta1 leads to protection from apoptosis and anchorage-independent growth. Oncogene. 2005;24(43):6564–73. doi:10.1038/sj.onc.1208798.PubMed

105.

Schulz R, Marchenko ND, Holembowski L, Fingerle-Rowson G, Pesic M, Zender L, et al. Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression. J Exp Med. 2012;209(2):275–89. doi:10.1084/jem.20111117.PubMedCentralPubMed

106.

Tania M, Khan MA, Fu J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer. Tumour Biol. 2014. doi:10.1007/s13277-014-2163-y.PubMed

107.

Mendillo ML, Santagata S, Koeva M, Bell GW, Hu R, Tamimi RM, et al. HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell. 2012;150(3):549–62. doi:10.1016/j.cell.2012.06.031.PubMedCentralPubMed

108.

St-Laurent V, Sanchez M, Charbonneau C, Tremblay A. Selective hormone-dependent repression of estrogen receptor beta by a p38-activated ErbB2/ErbB3 pathway. J Steroid Biochem Mol Biol. 2005;94(1–3):23–37. doi:10.1016/j.jsbmb.2005.02.001.PubMed

109.

Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29(2):217–33. doi:10.1210/er.2006-0045.PubMedCentralPubMed

110.

Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003;95(2):142–53.PubMed

111.

Green CA, Peter MB, Speirs V, Shaaban AM. The potential role of ER beta isoforms in the clinical management of breast cancer. Histopathology. 2008;53(4):374–80. doi:10.1111/j.1365-2559.2008.02968.x.PubMed

112.

Omoto Y, Eguchi H, Yamamoto-Yamaguchi Y, Hayashi S. Estrogen receptor (ER) beta1 and ERbetacx/beta2 inhibit ERalpha function differently in breast cancer cell line MCF7. Oncogene. 2003;22(32):5011–20. doi:10.1038/sj.onc.1206787.PubMed

113.

Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-Ashry D. Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res. 2006;66(7):3903–11. doi:10.1158/0008-5472.CAN-05-4363.PubMed

114.

Oh AS, Lorant LA, Holloway JN, Miller DL, Kern FG, El-Ashry D. Hyperactivation of MAPK induces loss of ERalpha expression in breast cancer cells. Mol Endocrinol. 2001;15(8):1344–59. doi:10.1210/mend.15.8.0678.PubMed

115.

Lin Fde M, Pincerato KM, Bacchi CE, Baracat EC, Carvalho FM. Coordinated expression of oestrogen and androgen receptors in HER2-positive breast carcinomas: impact on proliferative activity. J Clin Pathol. 2012;65(1):64–8. doi:10.1136/jclinpath-2011-200318.PubMed

116.

Nielsen TO, Andrews HN, Cheang M, Kucab JE, Hsu FD, Ragaz J, et al. Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res. 2004;64(1):286–91.PubMed

117.

Karamouzis MV, Papavassiliou AG. Targeting insulin-like growth factor in breast cancer therapeutics. Crit Rev Oncol Hematol. 2012;84(1):8–17. doi:10.1016/j.critrevonc.2012.02.010.PubMed

118.

Baxi SM, Tan W, Murphy ST, Smeal T, Yin MJ. Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. PLoS One. 2012;7(10):e48402. doi:10.1371/journal.pone.0048402.PubMedCentralPubMed

119.

Haluska P, Carboni JM, TenEyck C, Attar RM, Hou X, Yu C, et al. HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther. 2008;7(9):2589–98. doi:10.1158/1535-7163.MCT-08-0493.PubMedCentralPubMed

120.

Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65(23):11118–28. doi:10.1158/0008-5472.CAN-04-3841.PubMed

121.

Huang X, Gao L, Wang S, McManaman JL, Thor AD, Yang X, et al. Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-i receptor in breast cancer cells resistant to herceptin. Cancer Res. 2010;70(3):1204–14. doi:10.1158/0008-5472.CAN-09-3321.PubMed

122.

Worthington J, Bertani M, Chan HL, Gerrits B, Timms JF. Transcriptional profiling of ErbB signaling in mammary luminal epithelial cells–interplay of ErbB and IGF1 signaling through IGFBP3 regulation. BMC Cancer. 2010;10:490. doi:10.1186/1471-2407-10-490.PubMedCentralPubMed

123.

Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, et al. Protein tyrosine phosphatases in the human genome. Cell. 2004;117(6):699–711. doi:10.1016/j.cell.2004.05.018.PubMed

124.

Nunes-Xavier CE, Martin-Perez J, Elson A, Pulido R. Protein tyrosine phosphatases as novel targets in breast cancer therapy. Biochim Biophys Acta. 2013;1836(2):211–26. doi:10.1016/j.bbcan.2013.06.001.PubMed

125.

Yuan T, Wang Y, Zhao ZJ, Gu H. Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. J Biol Chem. 2010;285(20):14861–70. doi:10.1074/jbc.M109.099879.PubMedCentralPubMed

126.

Yu M, Lin G, Arshadi N, Kalatskaya I, Xue B, Haider S, et al. Expression profiling during mammary epithelial cell three-dimensional morphogenesis identifies PTPRO as a novel regulator of morphogenesis and ErbB2-mediated transformation. Mol Cell Biol. 2012;32(19):3913–24. doi:10.1128/MCB. 00068-12.PubMedCentralPubMed

127.

Vermeer PD, Bell M, Lee K, Vermeer DW, Wieking BG, Bilal E, et al. ErbB2, EphrinB1, Src kinase and PTPN13 signaling complex regulates MAP kinase signaling in human cancers. PLoS One. 2012;7(1):e30447. doi:10.1371/journal.pone.0030447.PubMedCentralPubMed

128.

Glondu-Lassis M, Dromard M, Lacroix-Triki M, Nirde P, Puech C, Knani D, et al. PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase. Cancer Res. 2010;70(12):5116–26. doi:10.1158/0008-5472.CAN-09-4368.PubMedCentralPubMed

129.

Revillion F, Puech C, Rabenoelina F, Chalbos D, Peyrat JP, Freiss G. Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent prognostic marker for overall survival in breast cancer. Int J Cancer. 2009;124(3):638–43. doi:10.1002/ijc.23989.PubMedCentralPubMed

130.

Julien SG, Dube N, Read M, Penney J, Paquet M, Han Y, et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet. 2007;39(3):338–46. doi:10.1038/ng1963.PubMed

131.

Arias-Romero LE, Saha S, Villamar-Cruz O, Yip SC, Ethier SP, Zhang ZY, et al. Activation of Src by protein tyrosine phosphatase 1B Is required for ErbB2 transformation of human breast epithelial cells. Cancer Res. 2009;69(11):4582–8. doi:10.1158/0008-5472.CAN-08-4001.PubMedCentralPubMed

132.

Wiener JR, Kerns BJ, Harvey EL, Conaway MR, Iglehart JD, Berchuck A, et al. Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. J Natl Cancer Inst. 1994;86(5):372–8.PubMed

133.

Soysal S, Obermann EC, Gao F, Oertli D, Gillanders WE, Viehl CT, et al. PTP1B expression is an independent positive prognostic factor in human breast cancer. Breast Cancer Res Treat. 2013;137(2):637–44. doi:10.1007/s10549-012-2373-1.PubMed

134.

Boivin B, Chaudhary F, Dickinson BC, Haque A, Pero SC, Chang CJ, et al. Receptor protein-tyrosine phosphatase alpha regulates focal adhesion kinase phosphorylation and ErbB2 oncoprotein-mediated mammary epithelial cell motility. J Biol Chem. 2013;288(52):36926–35. doi:10.1074/jbc.M113.527564.PubMedCentralPubMed

135.

Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, et al. TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 2014;106(2):djt369. doi:10.1093/jnci/djt369.PubMedCentralPubMed

136.

Wang SE, Shin I, Wu FY, Friedman DB, Arteaga CL. HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor beta. Cancer Res. 2006;66(19):9591–600. doi:10.1158/0008-5472.CAN-06-2071.PubMed

137.

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. doi:10.1158/0008-5472.CAN-08-2649.PubMedCentralPubMed

138.

Daniels RH, Bokoch GM. p21-activated protein kinase: a crucial component of morphological signaling? Trends Biochem Sci. 1999;24(9):350–5.PubMed

139.

Kass L, Erler JT, Dembo M, Weaver VM. Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int J Biochem Cell Biol. 2007;39(11):1987–94. doi:10.1016/j.biocel.2007.06.025.PubMedCentralPubMed

140.

Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, et al. Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. EMBO J. 2000;19(2):263–72. doi:10.1093/emboj/19.2.263.PubMedCentralPubMed

141.

Koromilas AE, Sexl V. The tumor suppressor function of STAT1 in breast cancer. Jak-Stat. 2013;2(2):e23353. doi:10.4161/jkst.23353.PubMedCentralPubMed

142.

Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol. 1997;17(9):5328–37.PubMedCentralPubMed

143.

Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997;278(5343):1630–2.PubMed

144.

Huang S, Bucana CD, Van Arsdall M, Fidler IJ. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene. 2002;21(16):2504–12. doi:10.1038/sj.onc.1205341.PubMed

145.

Wenta N, Strauss H, Meyer S, Vinkemeier U. Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations. Proc Natl Acad Sci U S A. 2008;105(27):9238–43. doi:10.1073/pnas.0802130105.PubMedCentralPubMed

146.

Raven JF, Williams V, Wang S, Tremblay ML, Muller WJ, Durbin JE, et al. Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation. Cell Cycle. 2011;10(5):794–804.PubMed

147.

Han W, Carpenter RL, Cao X, Lo HW. STAT1 gene expression is enhanced by nuclear EGFR and HER2 via cooperation with STAT3. Mol Carcinog. 2013;52(12):959–69. doi:10.1002/mc.21936.PubMed

148.

Liao JY, Li LL, Wei Q, Yue JC. Heregulinbeta activates store-operated Ca2+ channels through c-erbB2 receptor level-dependent pathway in human breast cancer cells. Arch Biochem Biophys. 2007;458(2):244–52. doi:10.1016/j.abb.2006.12.003.PubMed

149.

White CD, Li Z, Sacks DB. Calmodulin binds HER2 and modulates HER2 signaling. Biochim Biophys Acta. 2011;1813(5):1074–82. doi:10.1016/j.bbamcr.2010.12.016.PubMedCentralPubMed

150.

Li H, Sanchez-Torres J, Del Carpio A, Salas V, Villalobo A. The ErbB2/Neu/HER2 receptor is a new calmodulin-binding protein. Biochem J. 2004;381(Pt 1):257–66. doi:10.1042/BJ20040515.PubMedCentralPubMed

151.

Xu C, Chen H, Wang X, Gao J, Che Y, Li Y, et al. S100A14, a member of the EF-hand calcium-binding proteins, is overexpressed in breast cancer and acts as a modulator of HER2 signaling. J Biol Chem. 2014;289(2):827–37. doi:10.1074/jbc.M113.469718.PubMedCentralPubMed

152.

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 Off Publ Fed Am Soc Exp Biol. 2014;28(1):350–63. doi:10.1096/fj.13-233288.

153.

Lauritzen G, Stock C-M, Lemaire J, Lund SF, Jensen MF, Damsgaard B, et al. The Na+/H+ exchanger NHE1, but not the Na+, cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2. Cancer Lett. 2012;317(2):172–83. doi:10.1016/j.canlet.2011.11.023.PubMed

154.

Mills IG. Nuclear translocation and functions of growth factor receptors. Semin Cell Dev Biol. 2012;23(2):165–71. doi:10.1016/j.semcdb.2011.09.004.PubMed

155.

Wang SC, Lien HC, Xia WY, Chen IF, Lo HW, Wang ZQ, et al. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell. 2004;6(3):251–61. doi:10.1016/j.ccr.2004.07.012.PubMed

156.

Schillaci R, Guzman P, Cayrol F, Beguelin W, Diaz Flaque MC, Proietti CJ, et al. Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer. BMC Cancer. 2012;12:74. doi:10.1186/1471-2407-12-74.PubMedCentralPubMed

157.

Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ. Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem. 2002;277(21):18649–57. doi:10.1074/jbc.M111415200.PubMed

158.

Diaz Flaque MC, Galigniana NM, Beguelin W, Vicario R, Proietti CJ, Russo RC, et al. Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy. Breast Cancer Res. 2013;15(6):R118. doi:10.1186/bcr3587.PubMedCentralPubMed

159.

Cancer Research UK. Breast cancer statistics. 2010. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/. Accessed 21 Oct 2013.

160.

Boyle P. Triple-negative breast cancer: epidemiological considerations and recommendations. Ann Oncol. 2012;23 Suppl 6:vi7–12. doi:10.1093/annonc/mds187.PubMed

161.

Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med. 2013;274(2):113–26. doi:10.1111/joim.12084.PubMedCentralPubMed

162.

Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719–26.PubMed

163.

Gampenrieder SP, Rinnerthaler G, Greil R. Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. J Oncol. 2013;2013:732047. doi:10.1155/2013/732047.PubMedCentralPubMed

164.

Yan M, Parker BA, Schwab R, Kurzrock R. HER2 aberrations in cancer: implications for therapy. Cancer Treat Rev. 2014. doi:10.1016/j.ctrv.2014.02.008.PubMed

165.

Allouche A, Nolens G, Tancredi A, Delacroix L, Mardaga J, Fridman V, et al. The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors. Breast Cancer Res. 2008;10(1):R9. doi:10.1186/bcr1851.PubMedCentralPubMed

166.

Nolens G, Pignon JC, Koopmansch B, Elmoualij B, Zorzi W, De Pauw E, et al. Ku proteins interact with activator protein-2 transcription factors and contribute to ERBB2 overexpression in breast cancer cell lines. Breast Cancer Res. 2009;11(6):R83. doi:10.1186/bcr2450.PubMedCentralPubMed

167.

Matsui K, Sugimori K, Motomura H, Ejiri N, Tsukada K, Kitajima I. PEA3 cooperates with c-Jun in regulation of HER2/neu transcription. Oncol Rep. 2006;16(1):153–8.PubMed

168.

Kalra J, Sutherland BW, Stratford AL, Dragowska W, Gelmon KA, Dedhar S, et al. Suppression of Her2/neu expression through ILK inhibition is regulated by a pathway involving TWIST and YB-1. Oncogene. 2010;29(48):6343–56. doi:10.1038/onc.2010.366.PubMedCentralPubMed

169.

Ghosh A, Awasthi S, Hamburger AW. ErbB3-binding protein EBP1 decreases ErbB2 levels via a transcriptional mechanism. Oncol Rep. 2013;29(3):1161–6. doi:10.3892/or.2012.2186.PubMedCentralPubMed

170.

Zhang T, Zhang H, Wang Y, McGown LB. Capture and identification of proteins that bind to a GGA-rich sequence from the ERBB2 gene promoter region. Anal Bioanal Chem. 2012;404(6–7):1867–76. doi:10.1007/s00216-012-6322-y.PubMed

171.

Bose R, Molina H, Patterson AS, Bitok JK, Periaswamy B, Bader JS, et al. Phosphoproteomic analysis of Her2/neu signaling and inhibition. Proc Natl Acad Sci U S A. 2006;103(26):9773–8. doi:10.1073/pnas.0603948103.PubMedCentralPubMed

Title: The HER2 Signaling Network in Breast Cancer—Like a Spider in its Web
Authors: A. Dittrich
H. Gautrey
D. Browell
A. Tyson-Capper
Publication date: 01-12-2014
Publisher: Springer US
Published in: Journal of Mammary Gland Biology and Neoplasia / Issue 3-4/2014
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI: https://doi.org/10.1007/s10911-014-9329-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3-4/2014

The National Mastitis Council: A Global Organization for Mastitis Control and Milk Quality, 50 Years and Beyond

Bioactive Functions of Milk Proteins: a Comparative Genomics Approach

Unsolved Mysteries of the Human Mammary Gland: Defining and Redefining the Critical Questions from the Lactation Consultant’s Perspective

Exosomes Derived from Breast Cancer Cells, Small Trojan Horses?

Keynote webinar | Spotlight on antibody–drug conjugates in cancer