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Understanding EGFR Signaling in Breast Cancer and Breast Cancer Stem Cells: Overexpression and Therapeutic Implications
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 Title & Authors
Understanding EGFR Signaling in Breast Cancer and Breast Cancer Stem Cells: Overexpression and Therapeutic Implications
Alanazi, Ibrahim O; Khan, Zahid;
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Epidermal growth factor receptors (EGFRs/HERs) and downstream signaling pathways have been implicated in the pathogenesis of several malignancies including breast cancer and its resistance to treatment with chemotherapeutic drugs. Consequently, several monoclonal antibodies as well as small molecule inhibitors targeting these pathways have emerged as therapeutic tools in the recent past. However, studies have shown that utilizing these molecules in combination with chemotherapy has yielded only limited success. This review describes the current understanding of EGFRs/HERs and associated signaling pathways in relation to development of breast cancer and responses to various cancer treatments in the hope of pointing to improved prevention, diagnosis and treatment. Also, we review the role of breast cancer stem cells (BCSCs) in disease and the potential to target these cells.
Breast cancer;epithelial growth factor receptors;breast cancer stem cells;MAbs;TKI;
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Asian Pacific Journal of Cancer Prevention, 2016. vol.17. 7, pp.3053-3060 crossref(new window)
ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin, Nature Communications, 2017, 8, 1  crossref(new windwow)
Agus DB, Akita RW, Fox WD, et al (2002). Targeting ligandactivated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell, 2, 127-37. crossref(new window)

Al-Hajj M, Wicha MS, Benito-Hernandez A, et al (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA, 100, 3983-8. crossref(new window)

Amiri-Kordestani L, Blumenthal GM, Xu QC, et al (2014). FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res, 20, 4436-41. crossref(new window)

Anderson NG, Ahmad T, Chan K, et al (2001). ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int J Cancer, 94, 774-82. crossref(new window)

Baselga J (2001). Phase I and II clinical trials of trastuzumab. Ann Oncol, 12, 49-55.

Basu A (2008). Molecular targets of breast cancer: AKTing in concert. Breast Cancer: Basic Clin Res, 2, 11-6.

Bouchalova K, Cizkova M, Cwiertka K, et al (2009). Triple negative breast cancer--current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment. Biomedical papers of the Medical Faculty of the University Palacky. Olomouc, Czechoslovakia, 153, 13-7. crossref(new window)

Brand TM, Iida M, Li CR, et al (2011). The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discovery Medicine, 66, 419-32.

Brennan M, Lim B (2015). The actual role of receptors as cancer markers, biochemical and clinical aspects: receptors in breast cancer. Adv Exp Med Biol, 867, 327-37. crossref(new window)

Burgess AW, Henis YI, Hynes NE, et al (2014). EGF receptor family: twisting targets for improved cancer therapies. Growth Factors, 32, 74-81. crossref(new window)

Canonici A, Gijsen M, Mullooly M, et al (2013). Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget, 4, 1592-605. crossref(new window)

Carpenter G, Cohen S (1979). Epidermal growth factor. Annu Rev Biochem, 48, 193-216. crossref(new window)

Cho HS, Mason K, Ramyar KX, et al (2003). Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature, 421, 756-60. crossref(new window)

Dhomen NS, Mariadason J, Tebbutt N, et al (2012). Therapeutic targeting of the epidermal growth factor receptor in human cancer. Crit Rev Oncog, 17, 31-50. crossref(new window)

Dick JE (2003). Breast cancer stem cells revealed. Proc Natl Acad Sci USA, 100, 3547-9. crossref(new window)

Dimitrakopoulos FI, Kottorou A, Antonacopoulou AG, et al (2015). Early-stage breast cancer in the elderly: confronting an old clinical problem. J Breast Cancer, 18, 207-17. crossref(new window)

Dontu G (2008). Breast cancer stem cell markers - the rocky road to clinical applications. Breast cancer research : BCR, 10, 110. crossref(new window)

Dragu DL, Necula LG, Bleotu C, et al (2015). Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells, 7, 1185-201.

Ennis BW, Lippman ME, Dickson RB (1991). The EGF receptor system as a target for antitumor therapy. Cancer Invest, 9, 553-62. crossref(new window)

Ettinger DS (2006). Clinical implications of EGFR expression in the development and progression of solid tumors: focus on non-small cell lung cancer. Oncologist, 11, 358-73. crossref(new window)

Fan Z, Baselga J, Masui H, et al (1993). Antitumor effect of antiepidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res, 53, 4637-42.

Foy KC, Wygle RM, Miller MJ, et al (2013). Peptide vaccines and peptidomimetics of EGFR (HER-1) ligand binding domain inhibit cancer cell growth in vitro and in vivo. J Immunol, 191, 217-27. crossref(new window)

Gancberg D, Jarvinen T, di Leo A, et al (2002). Evaluation of HER-2/NEU protein expression in breast cancer by immunohistochemistry: an interlaboratory study assessing the reproducibility of HER-2/NEU testing. Breast Cancer Res Treat, 74, 113-20. crossref(new window)

Geyer CE, Forster J, Lindquist D, et al (2006). Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med, 355, 2733-43. crossref(new window)

Ginestier C, Hur MH, Charafe-Jauffret E, et al (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 1, 555-67. crossref(new window)

Gingras AC, Kennedy SG, O'Leary MA, et al (1998). 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev, 12, 502-13. crossref(new window)

Harris RC, Chung E, Coffey RJ (2003). EGF receptor ligands. Exp Cell Res, 284, 2-13. crossref(new window)

Herbst RS, Bunn PA, Jr. (2003). Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res, 9, 5813-24.

Huang L, Fu L (2015). Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharm Sin B, 5, 390-401. crossref(new window)

Iorio MV, Ferracin M, Liu CG, et al (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Res, 65, 7065-70. crossref(new window)

Iqbal N, Iqbal N (2014). Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int, 2014, 852748.

Kamath S, Buolamwini JK (2006). Targeting EGFR and HER-2 receptor tyrosine kinases for cancer drug discovery and development. Medicinal Res Reviews, 26, 569-94. crossref(new window)

Kanematsu T, Yano S, Uehara H, et al (2003). Phosphorylation, but not overexpression, of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients. Oncol Res, 13, 289-98. crossref(new window)

Knowlden JM, Hutcheson IR, Jones HE, 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, 1032-44. crossref(new window)

Kondapaka SB, Fridman R, Reddy KB (1997). Epidermal growth factor and amphiregulin up-regulate matrix metalloproteinase-9 (MMP-9) in human breast cancer cells. Int J Cancer, 70, 722-6. crossref(new window)

Korkaya H, Paulson A, Iovino F, et al (2008). HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene, 27, 6120-30. crossref(new window)

Kute T, Lack CM, Willingham M, et al (2004). Development of Herceptin resistance in breast cancer cells. Cytometry A, 57, 86-93.

Lau YK, Du X, Rayannavar V, et al (2014). Metformin and erlotinib synergize to inhibit basal breast cancer. Oncotarget, 5, 10503-17. crossref(new window)

Li X, Lewis MT, Huang J, et al (2008). Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst, 100, 672-9. crossref(new window)

Liu Y, Chen C, Qian P, et al (2015). Gd-metallofullerenol nanomaterial as non-toxic breast cancer stem cell-specific inhibitor. Nat Commun, 6, 5988 crossref(new window)

Lyon, France (2013). International Agency for Research on Cancer.

Madrid MA, Lo RW (2004). Chromogenic in situ hybridization (CISH): a novel alternative in screening archival breast cancer tissue samples for HER-2/neu status. Breast Cancer Res, 6, 593-600. crossref(new window)

Marquez A, Wu R, Zhao J, et al (2004). Evaluation of epidermal growth factor receptor (EGFR) by chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) in archival gliomas using bright-field microscopy. Diagnostic Molec Path, 13, 1-8. crossref(new window)

Martinelli E, De Palma R, Orditura M, et al (2009). Antiepidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol, 158, 1-9.

Mayo LD, Donner DB (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA, 98, 11598-603. crossref(new window)

Menard S, Pupa SM, Campiglio M, et al (2003). Biologic and therapeutic role of HER2 in cancer. Oncogene, 22, 6570-8. crossref(new window)

Mendelsohn J (1997). Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res, 3, 2703-7.

Mendelsohn J (2000). Blockade of receptors for growth factors:an anticancer therapy--the fourth annual joseph H burchenal american association of cancer research clinical research award lecture. Clin Cancer Res, 6, 747-53.

Mendez MJ, Green LL, Corvalan JR, et al (1997). Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nature Genetics, 15, 146-56. crossref(new window)

Miki Y, Swensen J, Shattuck-Eidens D, et al (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 266, 66-71. crossref(new window)

Morrison BJ, Schmidt CW, Lakhani SR, et al (2008). Breast cancer stem cells: implications for therapy of breast cancer. Breast Cancer Res, 10, 210. crossref(new window)

Nahta R, Hung MC, Esteva FJ (2004). The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res, 64, 2343-6. crossref(new window)

Nicholson RI, Hutcheson IR, Harper ME, et al (2002). Modulation of epidermal growth factor receptor in endocrine-resistant, estrogen-receptor-positive breast cancer. Ann N Y Acad Sci, 963, 104-15.

Nicholson RI, Hutcheson IR, Knowlden JM, et al (2004). Nonendocrine pathways and endocrine resistance:observations with antiestrogens and signal transduction inhibitors in combination. Clin Cancer Res, 10, 346-54. crossref(new window)

Normanno N, De Luca A, Bianco C, et al (2006). Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 366, 2-16. crossref(new window)

O'Sullivan CC, Bradbury I, Campbell C, et al (2015). Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors crossref(new window)

Park CY, Tseng D, Weissman IL (2009). Cancer stem celldirected therapies: recent data from the laboratory and clinic. Mol Ther, 17, 219-30. crossref(new window)

Prenzel N, Fischer OM, Streit S, et al (2001). The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer, 8, 11-31. crossref(new window)

Rhodes A, Jasani B, Anderson E, et al (2002). Evaluation of HER-2/neu immunohistochemical assay sensitivity and scoring on formalin-fixed and paraffin-processed cell lines and breast tumors: a comparative study involving results from laboratories in 21 countries. Am J Clin Pathol, 118, 408-17. crossref(new window)

Ring A, Wheatley D, Hatcher H, et al (2014). Phase I study to assess the combination of afatinib with trastuzumab in patients with advanced or metastatic HER2-positive breast cancer. Clin Cancer Res, 21, 2737-44

Ruddon RW 2007. Cancer Biology, Oxford, Oxford University Press Inc.

Saura C, Garcia-Saenz JA, Xu B, et al (2014). Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol, 32, 3626-33. crossref(new window)

Schramm A, De Gregorio N, Widschwendter P, et al (2015). Targeted therapies in HER2-positive breast cancer - a systematic review. Breast Care, 10, 173-8. crossref(new window)

Schulz DM, Bollner C, Thomas G, et al (2009). Identification of differentially expressed proteins in triple-negative breast carcinomas using DIGE and mass spectrometry. J Proteome Res, 8, 3430-8. crossref(new window)

Sergina NV, Rausch M, Wang D, et al (2007). Escape from HER-family tyrosine kinase inhibitor therapy by the kinaseinactive HER3. Nature, 445, 437-41. crossref(new window)

Shiovitz S, Korde LA (2015). Genetics of breast cancer: a topic in evolution. Ann Oncol, 26, 1291-9.

Slamon DJ, Clark GM, Wong SG, et al (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235, 177-82. crossref(new window)

Slamon DJ, Godolphin W, Jones LA, et al (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 244, 707-12. crossref(new window)

Tai W, Mahato R, Cheng K (2010). The role of HER2 in cancer therapy and targeted drug delivery. J Control Release, 146, 264-75. crossref(new window)

Twelves CJ, Stebbing J (2012). Being there for women with metastatic breast cancer. a pan-European patient survey. Ann Oncol, 23, 132-.

Valdehita A, Carmena MaJ, Bajo AM, et al (2012). RNA interference-directed silencing of VPAC1 receptor inhibits VIP effects on both EGFR and HER2 transactivation and VEGF secretion in human breast cancer cells. Molec Cellular Endocrinol, 348, 241-6. crossref(new window)

Vandevijver MJ, Peterse JL, Mooi WJ, et al (1988). Neu-protein overexpression in breast-cancer - association with comedotype ductal carcinoma insitu and limited prognostic value in stage-II breast-cancer. N Engl J Med, 319, 1239-45. crossref(new window)

Verma S, Miles D, Gianni L, et al (2012). Trastuzumab emtansine for HER2-positive advanced breast cancer. The New England journal of medicine, 367, 1783-91. crossref(new window)

Welslau M, Diéras V, Sohn J-H, et al (2014). Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Cancer, 120, 642-51. crossref(new window)

Zaha DC (2014). Significance of immunohistochemistry in breast cancer. World J Clin Oncol, 5, 382-92. crossref(new window)