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Major Signaling Pathways Involved in Breast Cancer

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Breast Cancer Metastasis and Drug Resistance

Abstract

Breast cancer is the leading cause of cancer-related mortality among women worldwide. Significant advancement has been made recently in delineating the cellular processes and signaling pathways involved in breast cancer. Cross-communication between different pathways allows cells to identify and respond appropriately to the extracellular environment. Cancer development is a gradual and complex process resulting from any disruption in these pathways that ultimately generates signals defining the required biological response. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases represents both key regulators of normal cellular development as well as critical players in the development of a variety of cancers including breast cancer. The aim of this book chapter is to give a broad overview of signal transduction networks such as Ras/Raf/MEK/ERK and the PI3K/AKT pathways that are controlled by the EGFR superfamily of receptors. The elucidation of these signaling pathways will further provide new insights in understanding the pathogenesis of breast cancer and targeting these pathways to combat against breast cancer development, progression, and metastasis.

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Abbreviations

AKT:

Protein kinase B

AREG:

Hereregulins

BTC:

Betacellulin

CREB:

CAMP response element-binding

EGF:

Epidermal Growth Factor

EGFR:

Epidermal Growth Factor Receptor

EPI:

Epiregulin

EPG:

Epigen

ER:

Estrogen Receptor

ERK:

Extracellular Signal-Regulated Kinase

Gata-1:

Globin transcription factor 1

GPCRS:

G protein coupled receptors

HB-EGF:

Heparin-binding EGF-like growth factor

HER-1/2/3/4::

Human Epidermal Growth Factor Receptor-1/2/3/4

MAPK:

Mitogen-Activated Protein Kinase

MEK:

Mitogen-Activated Protein Kinase Kinase

mTOR:

Mammalian target of rapamycin

NRG:

Neuregulin

PKC:

Protein Kinase C

PI3K:

Phosphoinositide 3-kinase

PTEN:

Phosphatase and tensin homolog

RTKs:

Receptor Tyrosine Kinases

TGF-α:

Transforming Growth Factor alpha

References

  1. American Cancer Society (2012) Breast cancer facts and figures. www.cancer.org. Assessed 18 Aug 2012

  2. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516

    CAS  PubMed  Google Scholar 

  3. García-García C, Ibrahim YH, Serra V, Calvo MT, Guzmán M, Grueso J, Aura C, Gauthier ML, Torretto C, Ly J, Francescutti V, O’Day DH (2003) Protein kinase calpha negatively regulates cell spreading and motility in MDA-MB-231 human breast cancer cells downstream of epidermal growth factor receptor. Biochem Biophys Res Commun 307:839–846

    Google Scholar 

  4. Hu C, Huang L, Gest C, Xi X, Janin A, Soria C, Li H, Lu H (2012) Opposite regulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression, cell-associated procoagulant activity and invasiveness in MDA-MB-231 cells. J Hematol Oncol 5:16

    CAS  PubMed  Google Scholar 

  5. Kufe DW (2012) MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncog. doi:10.1038/onc.2012.158

    Google Scholar 

  6. Naderi A, Meyer M, Dowhan DH (2012) Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer. Neoplasia 14:283–296

    CAS  PubMed  Google Scholar 

  7. Wang Z, Fukushima H, Inuzuka H, Wan L, Liu P, Gao D, Sarkar FH, Wei W (2012) Skp2 is a promising therapeutic target in breast cancer. Front Oncol 1:18702

    PubMed  Google Scholar 

  8. Xue G, Restuccia DF, Lan Q, Hynx D, Dirnhofer S, Hess D, Rüegg C, Hemmings BA (2012) Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-β signaling axes. Cancer Discov 2:59–248

    Google Scholar 

  9. Carpenter G (1987) Receptors for epidermal growth factor and other polypeptide mitogens. Ann Rev Biochem 56:881–914

    CAS  PubMed  Google Scholar 

  10. Bates SE, Fojo T (2005) Epidermal growth factor receptor inhibitors: a moving target? Clin Cancer Res 11:7203–7205

    CAS  PubMed  Google Scholar 

  11. Biswas DK, Cruz AP, Gansberger E, Pardee AB (2000) Epidermal growth factor-induced nuclear factor kappa B activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci 97:8542–8547

    CAS  PubMed  Google Scholar 

  12. Bolufer P, Lluch A, Molina R, Alberola V, Vazquez C, Padilla J, Garcia-Conde J, Llopis F, Guillem V (1993) Epidermal growth factor in human breast cancer, endometrial carcinoma and lung cancer. its relationship to epidermal growth factor receptor, estradiol receptor and tumor TNM. Clin Chim Acta 215:51–61

    CAS  PubMed  Google Scholar 

  13. Chrysogelos SA, Yarden RI, Lauber AH, Murphy JM (1994) Mechanisms of EGF receptor regulation in breast cancer cells. Breast Cancer Res Treat 31:227–236

    CAS  PubMed  Google Scholar 

  14. Gershtein ES, Ermilova VD, Kuz’mina ZV, Kuzlinskii NE, Letiagin VP (1996) Expression of epidermal growth factor receptors and their ligands in malignant tumors of the breast. Vestn Ross Akad Med Nauk 3:15–19

    PubMed  Google Scholar 

  15. Harari D, Yarden Y (2000) Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 19:6102–6114

    CAS  PubMed  Google Scholar 

  16. Jardines L, Weiss M, Fowble B, Greene M (1993) neu(c-erbB-2/HER2) and the epidermal growth factor receptor (EGFR) in breast cancer. Pathobiol 61:268–282

    CAS  Google Scholar 

  17. Lewis S, Locker A, Todd JH, Bell JA, Nicholson R, Elston CW, Blamey RW, Ellis IO (1990) Expression of epidermal growth factor receptor in breast carcinoma. J Clin Pathol 43:385–389

    CAS  PubMed  Google Scholar 

  18. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137

    CAS  PubMed  Google Scholar 

  19. Normanno N, Bianco C, De Luca A, Salomon DS (2001) The role of EGF-related peptides in tumor growth. Front Biosci 6:D685–D707

    CAS  PubMed  Google Scholar 

  20. Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19:3159–3167

    CAS  PubMed  Google Scholar 

  21. Carpenter G, Cohen S (1990) Epidermal growth factor. J Biol Chem 265:7709–7712

    CAS  PubMed  Google Scholar 

  22. Riese DJ, Kim ED, Elenius K, Buckley S, Klagsbrun M, Plowman GD, Stem DF (1996) The epidermal growth factor receptor couples transforming growth factor-alpha, heparin-binding epidermal growth factor like factor, and amphiregulin to neu, ErbB-3, and ErbB-4. J Biol Chem 271:20047–20052

    CAS  PubMed  Google Scholar 

  23. Shoyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ (1989) Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 243:1074–1076

    CAS  PubMed  Google Scholar 

  24. Elenius K, Paul S, Allison G, Sun J, Klagsbrun M (1997) Activation of HER4 by heparin-binding EGFlike growth factor stimulates chemotaxis but not proliferation. EMBO J 16:1268–1278

    CAS  PubMed  Google Scholar 

  25. Shelly M, Pinkas-Kramarski R, Guarino BC, Waterman H, Wang LM, Lyass L, Alimandi M, Kuo A, Bacus SS, Pierce JH, Andrews GC, Yarden Y (1998) Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes. J Biol Chem 273:10496–10505

    CAS  PubMed  Google Scholar 

  26. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Bush J, Godowski PJ (1997) Neuregulin 3 (NRG3): a novel neural tissue-enriched protein that binds and activated ErbB4. Proc Natl Acad Sci 94:9562–9567

    CAS  PubMed  Google Scholar 

  27. Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC, Yarden Y (1999) Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 18:2681–2689

    CAS  PubMed  Google Scholar 

  28. Yao W, Feng D, Bian W, Yang L, Li Y, Yang Z, Xiong Y, Zheng J, Zhai R, He J (2012) EBP50 inhibits EGF-induced breast cancer cell proliferation by locking EGFR phosphorylation. Amino Acids. doi:10.1007/s00726-012-1277-z

    Google Scholar 

  29. Berclaz G, Altermatt HJ, Rohrbach V, Siragusa A, Dreher E, Smith PD (2001) EGFR dependent expression of STAT3 (but not STAT1) in breast cancer. Int J Oncol 6:60–1155

    Google Scholar 

  30. Brand TM, Iida M, Li C, Wheeler DL (2011) The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discov Med 12:419–432

    PubMed  Google Scholar 

  31. Greco S, Muscella A, Elia MG, Salvatore P, Storelli C, Mazzotta A, Manca C, Marsigliante S (2003) Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells. J Cell Physiol 196:370–377

    CAS  PubMed  Google Scholar 

  32. Hernández M, Martín R, García-Cubillas MD, Maeso-Hernández P, Nieto ML (2010) Secreted PLA2 induces proliferation in astrocytoma through the EGF receptor: another inflammation-cancer link. Neuro Oncol 12:1014–1023

    PubMed  Google Scholar 

  33. Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Cho S, Kim JS, Kim JH, Choe JH, Nam SJ, Lee JE, Yang JH (2009) EGF-induced MMP-9 expression is mediated by the JAK3/ERK pathway, but not by the JAK3/STAT-3 pathway in a SKBR3 breast cancer cell line. Cell Signal 21:892–898

    CAS  PubMed  Google Scholar 

  34. Riggins RB, Thomas KS, Ta HQ, Wen J, Davis RJ, Schuh NR, Donelan SS, Owen KA, Gibson MA, Shupnik MA, Silva CM, Parsons SJ, Clarke R, Bouton AH (2006) Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer Res 66:7007–7015

    CAS  PubMed  Google Scholar 

  35. Wu J, Zhang B, Wu M, Li H, Niu R, Ying G, Zhang N (2010) Screening of a PKC zeta-specific kinase inhibitor PKCzI257.3 which inhibits EGF-induced breast cancer cell chemotaxis. Invest New Drugs 28:268–275

    CAS  PubMed  Google Scholar 

  36. Brand TM, Iida M, Wheeler DL (2011) Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Cancer Biol Ther 11:777–792

    CAS  PubMed  Google Scholar 

  37. Li N, Nguyen HH, Byrom M, Ellington AD (2011) Inhibition of cell proliferation by an anti-EGFR aptamer. PLoS ONE 6:20299

    Google Scholar 

  38. Yan XL, Fu CJ, Chen L, Qin JH, Zeng Q, Yuan HF, Nan X, Chen HX, Zhou JN, Lin YL, Zhang XM, Yu CZ, Yue W, Pei XT (2012) Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat 132:153–164

    CAS  PubMed  Google Scholar 

  39. Nahta R (2012) Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance. Curr Med Chem 19:1065–1075

    CAS  PubMed  Google Scholar 

  40. Rexer BN, Arteaga CL (2012) Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog 17:1–16

    PubMed  Google Scholar 

  41. Stark A, Kleer CG, Martin I, Awuah B, Nsiah-Asare A, Takyi V, Braman M, Quayson SE, Zarbo R, Wicha M, Newman L (2010) African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study. Cancer 116:4926–4932

    PubMed  Google Scholar 

  42. Bouché O, Penault-Llorca F (2010) HER2 and gastric cancer: a novel therapeutic target for Trastuzumab. Bull Cancer 97:1429–1440

    PubMed  Google Scholar 

  43. Burris HA 3rd, Tibbitts J, Holden SN, Sliwkowski MX, Lewis Phillips GD (2011) Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2 + breast cancer. Clin Breast Cancer 11:275–282

    CAS  PubMed  Google Scholar 

  44. Callahan R, Hurvitz S (2011) Human epidermal growth factor receptor-2-positive breast cancer: current management of early, advanced, and recurrent disease. Curr Opin Obstet Gynecol 23:37–43

    PubMed  Google Scholar 

  45. Pegram MD, Pauletti G, Slamon DJ (1998) HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 52:65–77

    CAS  PubMed  Google Scholar 

  46. Li YW, Zhu GY, Shen XL, Chu JH, Yu ZL, Fong WF (2011) Furanodienone induces cell cycle arrest and apoptosis by suppressing EGFR/HER2 signaling in HER2-overexpressing human breast cancer cells. Cancer Chemother Pharmacol 68:1315–1323

    CAS  PubMed  Google Scholar 

  47. Olivras-Ferraros C, Vazquez-Martin A, Cufí S, Torres-Garcia VZ, Sauri-Nadal T, Barco SD, Lopez-Bonet E, Brunet J, Martin-Castillo B, Menendez JA (2011) Inhibitor of apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies. Biochem Biophys Res Commun 407:412–419

    Google Scholar 

  48. Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL, Chamness GC, Rimawi MF, Osborne CK, Schiff R (2011) Different mechanisms for resistance to Trastuzumab versus lapatinib in HER2-positive breast cancers–role of estrogen receptor and HER2 reactivation. Breast Cancer Res 13:121

    Google Scholar 

  49. Fiorio E, Mercanti A, Terrasi M, Micciolo R, Remo A, Auriemma A, Molino A, Parolin V, Di Stefano B, Bonetti F, Giordano A, Cetto GL, Surmacz E (2008) Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis. BMC Cancer 8:305

    PubMed  Google Scholar 

  50. Ross JS, Fletcher JA (1999) The HER-2/neu oncogene: prognostic factor, predictive factor and target for therapy. Semin Cancer Biol 9:125–138

    CAS  PubMed  Google Scholar 

  51. Hicks DG, Kulkarni S (2008) HER2 + breast cancer: review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol 129:263–273

    PubMed  Google Scholar 

  52. Akhdar A, Bronsard M, Lemieux R, Geha S (2011) HER-2 oncogene amplification assessment in invasive breast cancer by dual-color in situ hybridization (dc-CISH): a comparative study with fluorescent in situ hybridization (FISH). Ann Pathol 31:472–479

    PubMed  Google Scholar 

  53. Hojati Z, Orangi E (2012) HER-2/neu gene amplification assessment in breast cancer patients in Isfahan province by real time PCR, differential PCR and immunohistochemistry. Gene 497:237–242

    CAS  PubMed  Google Scholar 

  54. Ohlschlegel C, Zahel K, Kradolfer D, Hell M, Jochum W (2011) HER2 genetic heterogeneity in breast carcinoma. J Clin Pathol 64:1112–1116

    CAS  PubMed  Google Scholar 

  55. Press MF, Slamon DJ, Flom KJ, Park J, Zhou JY, Bernstein L (2002) Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol 20:3095–3105

    CAS  PubMed  Google Scholar 

  56. Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, Sliwkowski MX (2006) Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother 55:717–727

    CAS  PubMed  Google Scholar 

  57. Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM et al (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144:1032–1044

    CAS  PubMed  Google Scholar 

  58. Kong A, Calleja V, Leboucher P, Harris A, Parker PJ, Larijani B (2008) HER2 oncogenic function escapes EGFR tyrosine kinase inhibitors via activation of alternative HER receptors in breast cancer cells. PLoS ONE 3:2881

    Google Scholar 

  59. Gallardo A, Lerma E, Escuin D, Tibau A, Muñoz J, Ojeda B, Barnadas A, Adrover E, Sánchez-Tejada L, Giner D, Ortiz-Martínez F, Peiró G (2012) Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with Trastuzumab resistance in HER2 breast carcinomas. Br J Cancer 106:1367–1373

    CAS  PubMed  Google Scholar 

  60. Lee CC, Yang HL, Way TD, Kumar KJ, Juan YC, Cho HJ, Lin KY, Hsu LS, Chen SC, Hseu YC (2012) Inhibition of cell growth and induction of apoptosis by antrodia camphorata in HER-2/neu-overexpressing breast cancer cells through the induction of ROS, depletion of HER-2/neu, and disruption of the PI3K/Akt signaling pathway. Evid Based Complement Alternat Med 2012:702857

    PubMed  Google Scholar 

  61. Nahta R, O’Regan RM (2010) Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. Clin Breast Cancer Suppl 3:72–78

    Google Scholar 

  62. Puglisi F, Minisini AM, De Angelis C, Arpino G (2012) Overcoming treatment resistance in HER2-positive breast cancer: potential strategies. Drugs 72:1175–1193

    CAS  PubMed  Google Scholar 

  63. Xiang B, Chatti K, Qiu H, Lakshmi B, Krasnitz A, Hicks J, Yu M, Miller WT, Muthuswamy SK (2008) Brk is coamplified with ErbB2 to promote proliferation in breast cancer. Proc Natl Acad Sci U S A 105:12463–12468

    CAS  PubMed  Google Scholar 

  64. Liao D, Liu Z, Wrasidlo WJ, Luo Y, Nguyen G, Chen T, Xiang R, Reisfeld RA (2011) Targeted therapeutic remodeling of the tumor microenvironment improves an HER-2 DNA vaccine and prevents recurrence in a murine breast cancer model. Cancer Res 71:5688–5696

    CAS  PubMed  Google Scholar 

  65. Lin L, Hutzen B, Ball S, Foust E, Sobo M, Deangelis S, Pandit B, Friedman L, Li C, Li PK, Fuchs J, Lin J (2009) New curcumin analogues exhibit enhanced growth-suppressive activity and inhibit AKT and signal transducer and activator of transcription 3 phosphorylation in breast and prostate cancer cells. Cancer Sci 100:1719–1727

    CAS  PubMed  Google Scholar 

  66. Siddiqa A, Long LM, Li L, Marciniak RA, Kazhdan I (2008) Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways. BMC Cancer 8:129

    PubMed  Google Scholar 

  67. Tanizaki J, Okamoto I, Fumita S, Okamoto W, Nishio K, Nakagawa K (2011) Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification. Oncogene 30:4097–4106

    CAS  PubMed  Google Scholar 

  68. Xu L, Yin S, Banerjee S, Sarkar F, Reddy KB (2011) Enhanced anticancer effect of the combination of cisplatin and TRAIL in triple-negative breast tumor cells. Mol Cancer Ther 10:550–557

    CAS  PubMed  Google Scholar 

  69. Asanuma H, Torigoe T, Kamiguchi K, Hirohashi Y, Ohmura T, Hirata K, Sato M, Sato N (2005) Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells. Cancer Res 65:11018–11025

    CAS  PubMed  Google Scholar 

  70. Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham KM, Treece AL, Hardwicke MA, Dush M, Liao Q, Westlund RE, Zhao S, Bacus S, Spector NL (2006) Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res 66:1640–1647

    CAS  PubMed  Google Scholar 

  71. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L (2011) Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 9:16–32

    PubMed  Google Scholar 

  72. Awada A, Saliba W, Bozovic-Spasojevic I (2011) Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer. Drugs Today (Barc) 47:335–345

    CAS  Google Scholar 

  73. Eccles SA (2011) The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology. Int J Dev Biol 55:685–696

    PubMed  Google Scholar 

  74. Alvarez RH, Valero V, Hortobagyi GN (2010) Emerging targeted therapies for breast cancer. J Clin Oncol 28:3366–3379

    CAS  PubMed  Google Scholar 

  75. Castro AF, Campos T, Babcock JT, Armijo ME, Martínez-Conde A, Pincheira R, Quilliam LA (2012) M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells. J Cell Biochem 113:1253–1264

    CAS  PubMed  Google Scholar 

  76. Lan T, Chen Y, Sang J, Wu Y, Wang Y, Jiang L, Tao Y (2012) Type II cGMP-dependent protein kinase inhibits EGF-induced MAPK/JNK signal transduction in breast cancer cells. Oncol Rep 276:2039–2044. doi:10.3892/or.2012.1726 School of medical science and laboratory medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R

    Google Scholar 

  77. Vranic S, Gatalica Z, Wang ZY (2011) Update on the molecular profile of the MDA-MB-453 cell line as a model for apocrine breast carcinoma studies. Oncol Lett 2:1131–1137

    CAS  PubMed  Google Scholar 

  78. Friday BB, Adjei AA (2008) Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 14:342–346

    CAS  PubMed  Google Scholar 

  79. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310

    CAS  PubMed  Google Scholar 

  80. Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351:289–305

    CAS  PubMed  Google Scholar 

  81. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    CAS  PubMed  Google Scholar 

  82. Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Bäsecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM, McCubrey JA (2008) Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 22:686–707

    CAS  PubMed  Google Scholar 

  83. Lefloch R, Pouysségur J, Lenormand P (2009) Total ERK1/2 activity regulates cell proliferation. Cell Cycle 8(5):11–705

    Google Scholar 

  84. Marais R, Light Y, Paterson HF, Marshall CJ (1995) Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 14:3136–3145

    CAS  PubMed  Google Scholar 

  85. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Bäsecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM (2008) Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22:708–722

    CAS  PubMed  Google Scholar 

  86. McCubrey JA, Steelman LS, Abrams SL, Chappell WH, Russo S, Ove R, Milella M, Tafuri A, Lunghi P, Bonati A, Stivala F, Nicoletti F, Libra M, Martelli AM, Montalto G, Cervello M (2009) Emerging Raf inhibitors. Expert Opin Emerg Drugs 14:633–648

    CAS  PubMed  Google Scholar 

  87. Balan V, Leicht DT, Zhu J, Balan K, Kaplun A, Singh-Gupta V, Qin J, Ruan H, Comb MJ, Tzivion G (2006) Identification of novel in vivo Raf-1 phosphorylation sites mediating positive feedback Raf-1 regulation by extracellular signal-regulated kinase. Mol Biol Cell 17:1141–1153

    CAS  PubMed  Google Scholar 

  88. Brummer T, Naegele H, Reth M, Misawa Y (2003) Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf. Oncogene 22:8823–8834

    CAS  PubMed  Google Scholar 

  89. Catalanotti F, Reyes G, Jesenberger V, Galabova-Kovacs G, de MatosSimoes R, Carugo O, Baccarini M (2009) A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol 16:294–303

    CAS  PubMed  Google Scholar 

  90. Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17:215–224

    CAS  PubMed  Google Scholar 

  91. Davis RJ (1995) Transcriptional regulation by MAP kinases. Mol Reprod Dev 42:459–467

    CAS  PubMed  Google Scholar 

  92. Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Cappellini A, Ognibene A, McCubrey JA (2010) The emerging role of the phosphatiylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogensis. Biochim Biophys Act 1803:991–1002

    CAS  Google Scholar 

  93. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV, Blagosklonny MV (2010) The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging 2:344–352

    CAS  PubMed  Google Scholar 

  94. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA (2010) The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 1:89–103

    PubMed  Google Scholar 

  95. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ (2000) Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10:1201–1204

    CAS  PubMed  Google Scholar 

  96. Fletcher JI, Huang DC (2008) Controlling the cell death mediators Bax and Bak: puzzles and conundrums. Cell Cycle 7:39–44

    CAS  PubMed  Google Scholar 

  97. McCubrey JA, Steelman LS, Kempf CR, Chappell WH, Abrams SL, Stivala F, Malaponte G, Nicoletti F, Libra M, Bäsecke J, Maksimovic-Ivanic D, Mijatovic S, Montalto G, Cervello M, Cocco L, Martelli AM (2011) Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol 226:2762–2781

    CAS  PubMed  Google Scholar 

  98. Qi XJ, Wildey GM, Howe PH (2006) Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem 281:813–823

    CAS  PubMed  Google Scholar 

  99. Steelman LS, Navolanic PM, Sokolosky ML, Taylor JR, Lehmann BD, Chappell WH, Abrams SL, Wong EW, Stadelman KM, Terrian DM, Leslie NR, Martelli AM, Stivala F, Libra M, Franklin RA, McCubrey JA (2008) Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors. Oncogene 27:4086–4095

    CAS  PubMed  Google Scholar 

  100. Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J (2007) RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates Cap-dependent translation. J Biol Chem 282:14056–14064

    CAS  PubMed  Google Scholar 

  101. Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Tauton J, Hershey JW, Blenis J, Pende M, Sonenberg N (2006) The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J 25:2781–2791

    CAS  PubMed  Google Scholar 

  102. Tamburini J, Green AS, Chapuis N, Bardet V, Lacombe C, Mayeux P, Bouscary D (2009) Targeting translation in acute myeloid leukemia: a new paradigm for therapy? Cell Cycle 8:3893–3899

    CAS  PubMed  Google Scholar 

  103. Johnston SR (2006) Targeting downstream effectors of epidermal growth factor receptor/HER2 in breast cancer with either farnesyltransferase inhibitors or mTOR antagonists. Int J Gynecol Cancer 2:543–548

    Google Scholar 

  104. Hadzisejdić I, Mustać E, Jonjić N, Petković M, Grahovac B (2010) Nuclear EGFR in ductal invasive breast cancer: correlation with cyclin-D1 and prognosis. Mod Pathol 23:392–403

    PubMed  Google Scholar 

  105. Pitteri SJ, Amon LM, Busald Buson T, Zhang Y, Johnson MM, Chin A, Kennedy J, Wong CH, Zhang Q, Wang H, Lampe PD, Prentice RL, McIntosh MW, Hanash SM, Li CI (2010) Detection of elevated plasma levels of epidermal growth factor receptor before breast cancer diagnosis among hormone therapy users. Cancer Res 70:8598–8606

    CAS  PubMed  Google Scholar 

  106. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, Donia M, Fagone P, Malaponte G, Nicoletti F, Libra M, Milella M, Tafuri A, Bonati A, Bäsecke J, Cocco L, Evangelisti C, Martelli AM, Montalto G, Cervello M, McCubrey JA (2011) Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY) 3:192–222

    CAS  Google Scholar 

  107. Kacinski BM, Scata KA, Carter D, Yee LD, Sapi E, King BL, Chambers SK, Jones MA, Pirro MH, Stanley BR, Rohrschneider LR (1991) FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene 6:941–952

    CAS  PubMed  Google Scholar 

  108. Kacinski BM (1995) CSF-1 and its receptor in ovarian, endometrial and breast cancer. Ann Med 27:79–85

    CAS  PubMed  Google Scholar 

  109. Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Biegel JA, Hayes RL, Wong AJ (1995) Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 55:5536–5539

    CAS  PubMed  Google Scholar 

  110. Gangarosa LM, Sizemore N, Graves-Deal R, Oldham SM, Der CJ, Coffey RJ (1997) A raf-independent epidermal growth factor receptor autocrine loop is necessary for Ras transformation of rat intestinal epithelial cells. J Biol Chem 272:18926–18931

    CAS  PubMed  Google Scholar 

  111. McCarthy SA, Samuels ML, Pritchard CA, Abraham JA, McMahon M (1995) Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. Genes Dev 9:1953–1964

    CAS  PubMed  Google Scholar 

  112. Schulze A, Lehmann K, Jefferies HB, McMahon M, Downward J (2001) Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev 15:981–994

    CAS  PubMed  Google Scholar 

  113. Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J (2004) The transcriptional response to Raf activation is almost completely dependent on mitogen-activated protein kinase kinase activity and shows a major autocrine component. Mol Biol Cell 15:3450–3463

    CAS  PubMed  Google Scholar 

  114. García-Echeverría C (2009) Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways. Purinergic Signal 5:117–125

    PubMed  Google Scholar 

  115. Saxena R, Dwivedi A (2012) ErbB family receptor inhibitors as therapeutic agents in breast cancer: current status and future clinical perspective. Med Res Rev 32:166–215

    CAS  PubMed  Google Scholar 

  116. Choi JH, Yang YR, Lee SK, Kim SH, Kim YH, Cha JY, Oh SW, Ha JR, Ryu SH, Suh PG (2008) Potential inhibition of PDK1/Akt signaling by phenothiazines suppresses cancer cell proliferation and survival. Ann N Y Acad Sci 1138:393–403

    CAS  PubMed  Google Scholar 

  117. Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644

    CAS  PubMed  Google Scholar 

  118. Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, Gunn S, Smetzer L, Mays TA, Kaiser B, Wick MJ, Alvarez C, Cavazos A, Mangold GL, Patnaik A (2012) The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 18:2316–2325

    CAS  PubMed  Google Scholar 

  119. van der Heijden MS, Bernards R (2010) Inhibition of the PI3K pathway: hope we can believe in? Clin Cancer Res 16:3094–3099

    PubMed  Google Scholar 

  120. Wong KK, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87–90

    CAS  PubMed  Google Scholar 

  121. Yi YW, Kang HJ, Kim HJ, Hwang JS, Wang A, Bae I (2012) Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells. Mol Carcinog. doi:10.1002/mc.21905

    PubMed  Google Scholar 

  122. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    CAS  PubMed  Google Scholar 

  123. Fruman DA, Meyers RE, Cantley LC (1998) Phosphoinositide kinases. Annu Rev Biochem 67:481–507

    CAS  PubMed  Google Scholar 

  124. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675

    CAS  PubMed  Google Scholar 

  125. Bader AG, Kang S, Zhao L, Vogt PK (2005) Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 5:921–929

    CAS  PubMed  Google Scholar 

  126. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

    CAS  PubMed  Google Scholar 

  127. Voigt P, Dorner MB, Schaefer M (2006) Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B. J Biol Chem 281:9977–9986

    CAS  PubMed  Google Scholar 

  128. Suire S, Coadwell J, Ferguson GJ, Davidson K, Hawkins P, Stephens L (2005) p84, a new Gbetagamma-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110gamma. Curr Biol 15:566–570

    CAS  PubMed  Google Scholar 

  129. Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2:760–768

    CAS  PubMed  Google Scholar 

  130. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    CAS  PubMed  Google Scholar 

  131. Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A, Bownes M (1997) 3-Phosphoinositide-dependent protein kinase-1 (PDK1). Curr Biol 7:776–789

    CAS  PubMed  Google Scholar 

  132. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT (1998) Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279:710–714

    CAS  PubMed  Google Scholar 

  133. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    CAS  PubMed  Google Scholar 

  134. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    CAS  PubMed  Google Scholar 

  135. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734

    CAS  PubMed  Google Scholar 

  136. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274

    CAS  PubMed  Google Scholar 

  137. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657

    CAS  PubMed  Google Scholar 

  138. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10:151–162

    CAS  PubMed  Google Scholar 

  139. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9:316–323

    CAS  PubMed  Google Scholar 

  140. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    CAS  PubMed  Google Scholar 

  141. Fedele CG, Ooms LM, Ho M, Vieusseux J, O’Toole SA, Millar EK, Lopez-Knowles E, Sriratana A, Gurung R, Baglietto L, Giles GG, Bailey CG, Rasko JE, Shields BJ, Price JT, Majerus PW, Sutherland RL, Tiganis T, McLean CA, Mitchell CA (2010) Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci 107:22231–22236

    CAS  PubMed  Google Scholar 

  142. Sadeq V, Isar N, Manoochehr T (2011) Association of sporadic breast cancer with PTEN/MMAC1/TEP1 promoter hypermethylation. Med Oncol 28:420–423

    CAS  PubMed  Google Scholar 

  143. She QB, Chandarlapaty S, Ye Q, Lobo J, Haskell KM, Leander KR, DeFeo-Jones D, Huber HE, Rosen N (2008) Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS ONE 3:3065

    Google Scholar 

  144. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091

    CAS  PubMed  Google Scholar 

  145. Miller TW, Balko JM, Arteaga CL (2011) Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 29:4452–4461

    CAS  PubMed  Google Scholar 

  146. Pérez J, Jessen K, Liu Y, Rommel C, Tabernero J, Baselga J, Scaltriti M (2012) Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 18:2603–2612

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Rush University Medical Center, 600 South Paulina Street Suite 507AcFac, Chicago, IL 60612, USA

    Moammir Hasan Aziz

  2. Department of Internal Medicine, Division of Endocrinology, Southern Illinois University School of Medicine, 751 N. Rutledge,  Springfield, IL 62794, USA

    Saba Wasim Aziz

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  1. Saba Wasim Aziz
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Correspondence to Moammir Hasan Aziz .

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  1. School of Medicine, Karmanos Cancer Institute, Wayne State University, John R Street 4100, Detroit, 48201, Michigan, USA

    Aamir Ahmad

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Aziz, S.W., Aziz, M.H. (2013). Major Signaling Pathways Involved in Breast Cancer. In: Ahmad, A. (eds) Breast Cancer Metastasis and Drug Resistance. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5647-6_4

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