Cellular Signaling Pathways in Breast Cancer

ISSN 1007-7626 CN 11-3870 / Q http / /cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology 2015 1 31 1 20 ~ 27 DOI 10 13865 /j cnki cjbmb 2015 01 04 * 116081 estrogen receptor ER insulin-like growth factor receptor IGFR epidermal growth factor receptor EGFR ER IGFR EGFR ER IGFR EGFR R736 3 Cellular Signaling Pathways in Breast Cancer SUI Jia-Qi XIE Kun-Peng XIE Ming-Jie * School of Life Sciences Liaoning Normal University Key Laboratory of Biotechnology and Molecular Drug Development of Liaoning Province Dalian 116081 Liaoning China Abstract Breast cancer is one of the most common malignant tumor in women Investigation of the occurrence development metastasis and the generation of multi-drug resistance of breast cancer are closely related to the intracellular signaling pathways Estrogen receptor ERα signaling pathway IGFR signaling pathway and EGFR signaling pathway and are particularly important Therefore understanding the mechanism of IGFR ERα EGFR signal pathway and the cross talk between them in depth are very important for seeking the new and more effective targets of tumor treatment This paper mainly reviewed the study of ER IGFR EGFR pathway and the relationship between these three pathways and breast cancer in recent years Key words breast cancer estrogen receptor ER insulin-like growth factor receptor IGFR epidermal growth factor receptor EGFR HER-2 20% ~ 30% 1 Luminal 3 estrogen receptor ER progestrone receptor PR 2 human epidermal growth factor receptor-2 HER-2 4 Luminal A Luminal B HER-2 2 Table 1 Luminal A Luminal B 50% ~ 60% 2014-08-18 2014-10-12 No L2013412 No 2013E13SF108 * Tel 13478958825 E-mail xmj1222@ sina com Received August 18 2014 Accepted October 12 2014 Supported by Scientific Research Projects of Department of Education Liaoning Province No L2013412 and Dalian Municipal Science and Technology Project No 2013E13SF108 tamoxifen TAM selective estrogen receptor modulators SERM * Corresponding author Tel + 86-13478958825 E-mail xmj1222@ sina com

1 21 HER-2 EGFR tmstuzumab hercepti EGFR DNA HER-2 7 HER-2 4 Luminal B Her-2 HER-2 triple-negative breast cancer TNBC 10% 5 6 EGFR Table 1 Breast cancer classification of molecular subtypes and treatment strategies Classification ER PR HER-2 Treatment strategies Representative drug Luminal A Positive Positive Negative Endocrine therapy TAM Anastrozole Luminal B Positive Positive Positive Endocrine therapy Chemotherapy Targeted therapy Herceptin HER-2 Negative Negative Positive Chemotherapy Herceptin Targeted therapy TNBC Negative Negative Negative Chemotherapy Mitoxantrone 1 1 1 ER 13 ERα ERβ ER ER ERα ERβ ERα /ERβ ERα 8 ERβ 9 ER HSP 1 2 ER HSP ER estrogen response element ERE Fuqua 10 11 ERs 14 ER ERα EGF IGF mrna ERα EGFR IGFR ER Song ERs 15 ERs 12 IGFR HB-EGF

22 31 EGFR MAPK insulin-like growth factor binding proteins IGFBPs 3 IGF-ⅠR IGF-ⅡR ER insulin receptor IR IGF-Ⅰ R Kurebayashi 16 IGF-ⅠR 20 ER PR IGF-1 IGF-1R 70% ~ 80% ER PR 10% ERα 150 P-Tyr IRS-1 insulin receptor tamoxifen TAM substrate-1 IRS-1 Tyr ERα 2 P-Tyr ERα36 ERα46 ERα36 36 kd ERα66 2 Ras-MAPK PI3K-Akt / AF-1 AF-2 PKB DNA ERα36 P-Tyr Shc IGF-ⅠR P-Tyr Grb2-SOS IGF-ⅠR ERα66 ERα36 ERα66 PDGF 17 Shi 18 896 EGF IGF-ⅠR ERα66 ERα36 IGF-ⅡR 2451 ERα ERβ Shaaban 19 880 ERβ1 2 5 IGF-ⅡR ERβ-2 ERβ IGF- Ⅱ IGF-ⅠR ERβ-5 21 2 2 2 IGF-1 IGF-1 IGF-1R 2 Worster 22 IGF-I EGF Akt ERK 2 1 23 40 IGF-Ⅰ insulin-like growth factor IGF-ⅠR IGF 2 IGF-1 IGF-II IGF-1R IGF-IIR 7 IGF IGF-Ⅰ IGF-ⅠR

1 23 80% 77 5% EGFR /HerbB1 / 27 5% 25% HER1 HerbB2 / HER2 / Neu HerbB3 / HER3 HerbB4 / Borowiec 24 MCF-7 HER4 29 EGFR 7q11 13 26 IGF-I D1 E 170 kd G 1 S Furukawa 25 IGF-1R mrna IGF-1R HER2 17q21 185 kd 2 670 30 HER3 /HerbB3 IGF-1 IGF-1R 12q13 mrna 6 2 kb 1 342 IGF-1 160 kd 31 HER3 DNA G 1 S IGF-1R HER2 HER2 Carboni HER3 HER2 26 IGF-1R 32 HER4 8 HER2 HER4 Benatar 27 33 IGFBP-7 G 1 EGFR -1 Dong 28 EGF MCF-7 IGF-1 EGF MAPK PI3 K / AKT EGF HB-EGF IGF-1 α TGF-α 34 EGFR Ras Raf MAPK Src AKT STAT3 /5 35 Ras-Raf-MAPK PI3K-PKC-IKK MAPK PI3K Src /STAT 3 2 EGFR 3 3 1 36 EGFR epidermal growth factor receptor EGFR N EGFR 37 Corkery 38 EGFR EGFR ER PR HER-2

24 31 EGFR 42 MCF-7 4 IGF-1R MMPs 2 9 HB-EGF HB-EGF EGFR 48 ER EGFR IGFR ERα IGF-1R IGF-1R IGF-1R IRS-1 IGFBP-3 49 Moore 50 IGF-1 EGF IGF- C50 1 IGF- IGF-1 IGF-1R EGFR 1R IRS-1 IRS-1 IGF-1 EGF EGFR HB-EGF TGFα mrna IGF-1 EGF MAPK IGF-1 EGFR ER COS-7 IGF1R MAPK 43 Castoria 44 cetuximab erbitux gefitinib iressa HerbB2 /Neu IGF-IR PI3K /Akt 20% ~ 30% IGF- 1R 39 HerbB2 IGF-1R ER ER HER2 IGF-1R ER MAPK PI3K / HER2 AKT Kahlert 45 ER HER3 EGFR HER2 IGF-1R Song 46 HER3 ERα Shc IGF1R HER3 MAPK ER Hereguli HER3 IGF-1 ER IGF-1 IGF-1R 40 IGF-1R Shc HER3 PI3K-AKT trans-activating RAS-MAPK EGFR HER2 IGF-1 ER IGF-1R HER3 Chiu E2 ERα 41 EGFR 47 EGFR ERα 4046 HER3 E2 EGF ICI182780 EGF ERα EGFR IGF-1R EGFR MAPK

1 25 HB-EGF mrna EGFR TGF-α mrna Western References IGF-1 EGF EGFR IGF-1R erbb2 IGF-1 3 EGF EGFR erbb2 IGF-1R cancer J clinicopathologic features and survival J in breast cancer treatment J ERα 2003 3 3 403 triple-negative tumors in an urban cancer center J EGFR HER-2 2008 113 3 608-615 EGFR HER-2 spread in triple-negative breast cancer J Treat 2009 115 2 423-428 51 p53 NF-κB BCRP 52 P- Her-2 P- Her-2 53 PI3K /AKT PI3K /AKT MCF-7 /ADR p53 NF-κB PI3K / AKT ERα IGFR EGFR ERα IGFR EGFR hormonal therapy J 1 Siegel R Naishadham D Jemal A Cancer statistics 2012 J CA Cancer J Clin 2012 62 1 10-29 2 Langerod A Zhou H Borgan O et al TP53 mutation status and gene expression profiles are powerful prognostic markers of breast Breast Cancer Res 2007 9 3 R30 3 Onitilo A A Engel J M Greenlee R T et al Breast cancer subtypes based on ER /PR and Her2 expression comparison of 2009 7 1-2 4-13 Clim Med Res 4 Untch M Ditsch N Hermelink K Immunotherapy new options Expert Rev Anticancer Ther 5 Lung M J Butler E N Bumpers H L et al High prevalence of ERα IGFR EGFR growth factor receptor type1 J 597-604 estrogen J Mol Endocrinol 2005 19 8 1951-1959 cancer J Cancer Res 1999 59 21 5425-5428 Cancer 6 Dent R Hanna W M Trudeau M et al Pattern of metastatic Breast Cancer Res 7 Baselga J Gomez P Awada A et al The addition of cetuximab to cisplatin increases overall response rate and progression-free survival in metastatic triple-negative breast cancer results of a randomized phase II study BALI-1 J Ann Oncol 2010 21 Suppl 8 viii96-viii121 8 Fox E M Bernaciak T M Wen J et al Signal transducer and activator of transcription 5b c-src and epidermal growth factor receptor signaling play integral roles in estrogen stimulated proliferation of estrogen receptor-positive breast cancer cells J Mol Endocrinol 2008 22 8 1781-1796 9 Fox E M Davis R J Shupnik M A ER beta in breast canceronlooker passive player or active protector J Steroids 2008 73 11 1039-1051 10 Hayashi S Yamaguchi Y Estrogen signaling pathway and Breast Cancer 2008 15 4 256-261 11 Levin E R Pietras R J Estrogen receptors outside the nucleus in breast cancer J Breast Cancer Res Treat 2008 108 3 351-361 12 Ueda S Tsuda H Sato K et al Alternative tyrosine phosphorylation of signaling kinases according to hormone receptor status in breast cancer over-expressing the insulin like Cancer Sci 2006 97 7 13 Levin E R Integration of the extra-nuclear and nuclear actions of 14 Fuqua S A Sehiff R Parra I et al Expression of wild-type estrogen receptor beta and variant isoforms in human breast 15 Song R X Zhang Z Chen Y et al Estrogen signaling via a linear pathway involving insulin-like growth factor I receptor matrix metalloproteinases and epidermal growth factor receptor to

26 31 activate mitogen-activated protein kinase in MCF-7 breast cancer cells J Endocrinology 2007 148 8 4091-4101 16 Kurebayashi J Current clinical trials of endocrine therapy for breast cancer J Breast Cancer 2007 14 2 200-214 17 Wang Z Zhang X Shen P et al A variant of estrogen receptoralpha ER-alpha36 transduction of estrogen- and antiestrogendependent membrane-initiated mitogenic signaling J Proc Natl Acad Sci U S A 2006 103 24 9063-9068 18 Shi L Dong B Li Z et al Expression of ER-36 a novel variant of estrogen receptor a and resistance to tamoxifen treatment in breast cancer J J Clin Oncol 2009 27 21 3423-3429 19 Shaaban A M Creen A R Karthik S et al Nuclear and cytoplasmic expression of ER-1-2 and -5 identifies distinct prognostic out-come for brat cancer patients J Clin Cancer Res 2008 14 16 5228-5235 20 Larsson O Girnita A Girnita L Role of insulin-like growth factor receptor signaling in cancer J Br J Cancer 2005 92 12 2097-2101 21 Scott C D Weiss J Soluble insulin-like growth factor II / mannose 6-phosphate receptor inhibits DNA synthesis in insulinlike growth factor II sensitive cells J J Cell Physiol 2000 182 1 62-68 22 Worster D T Schmelzle T Solimini N L et al Akt and ERK control the proliferative response of mammary epithelial cells to the growth factors IGF-1 and EGF through the cell cycle inhibitor p57kip2 J Sci Signal 2012 5 214 ra19 23 -Ⅰ mutations in resistance to EGFR inhibition in the treatment of J Wang J cancer J Curr Opin Investig Drugs 2009 10 12 1305- J Wang B M Fang W L et al The expression and significance 1314 of Insulin-like growth factor- I and its receptor in gastric carcinoma J J Gastroenterol Hepatol 2009 18 2 103-105 24 Borowiec A S Hague F Gouilleux-Gruart V et al Regulation of IGF-1-dependent cyclin D1 and E expression by heag1 channels in MCF-7 cells the critical role of heag1 channels in G1 phase progression J Biochim Biophys Acta 2011 1813 5 723-730 25 Furukawa M Raffeld M Mateo C et al Increased expression of insulin - like growth factor I and /or its receptor in gastrinomas is associated with low curability increased growth and development of metastases J Clin Cancer Res 2005 11 9 3233-3242 26 Carboni J M Lee A V Hadsell D L et al Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor J Cancer Res 2005 65 9 3781-3787 27 Benatar T Yang W Amemiya Y et al IGFBP7 reduces breast tumor growth by induction of senescence and apoptosis pathways J Breast Cancer Res Treat 2012 133 2 563-573 28 Dong S Inoue A Zhu Y et al Activation of rapid signaling pathways and the subsequent transcriptional regulation for the proliferation of breast cancer MCF-7 cells by the treatment with an extract of Glycyrrhiza glabra root J Food Chem Toxicol 2007 45 12 2470-2478 29 Foley J Nickerson N K Nam S et al EGFR signaling in breast cancer bad to the bone J Semin Cell Dev Biol 2010 21 9 951-960 30 Lohrish C Piccart M An overview of HER-2 J Semin Oncol 2001 28 6 Suppl 18 3-11 31 Bindels E M Vanderkwast T H Izadifar V et al Functions of epidermal growth factor-like growth factors during human urothelial reepithe1ia1ization in vitro and the role of erbb2 J Urol Res 2002 30 4 240-247 32 Sergina N V Rausch M Wang D et al Escape from HERfamily tyrosine kinase inhibitor therapy by the kinase-inactive HER3 J Nature 2007 445 7126 437-441 33 Kikuta T Shimazaki C Ashihara E et al Mobilization of hematopoietic primitive and committed progenitor cells into blood in mice by anti-vascular adhesion molecule-1 antibody alone or in combination with granulocyte colony-stimulating factor J Exp Hematol 2000 28 3 311-317 34 Li Y W Zhu G Y Shen X L et al Furanodienone induces cell cycle arrest and apoptosis by suppressing EGFR / HER2 signaling in HER2 over-expressing human breast cancer cells J Cancer Chemother Pharmacol 2011 68 5 1315-1323 35 Lemmon M A Sehleminger J Cell signaling by receptor tyrosine kinases J Cell 2010 141 7 1117-1134 36 Lopez-Clavez A Carter C A Giaccone G The role of KRAS 37 Coley H M Shotton C F Ajose-Adeogun A et al Receptor tyrosine kinase RTK inhibition is effective in chemosensitising EGFR-expressing drug resistant human ovarian cancer cell lines when used in combination with cytotoxic agents J Bioehem Pharmaco1 2006 72 8 941-948 38 Corkery B Crown J Clynes M et al Epidermal growth factor receptor as a potential therapeutic target in triple negative breast cancer J Ann Oncol 2009 20 7 862-867 39 Swiatoniowski G Dabrowska M Klaniewski T et al Erb-2 over-expression in breast cancer J Cinekol Pol 2003 74 4 332-338 40 Tsai M S Shamon-Taylor LA Mehmi I et al Block-age of heregulin expression inhibits tumorigenicity and metastasis of breast cancer J Oncogene 2003 22 5 761-768 41 Chiu C G Masoudi H Leung S et al HER3 over-expression is prognostic of reduced breast cancer survival a study of 4046 patients J Ann Surg 2010 251 6 1107-1116 42 Oesterreich S Zhang P Guler R L et al Re-expression of estrogen receptor αlpha in estrogen receptor αlpha-negative MCF- 7 cells restores both estrogen and insulin- like growth factor mediated signaling and growth J Cancer Res 2001 61 15 5771-5777

1 27 43 Kahlert S Nuedling S van Eickels M et al Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway J J Biol Chem 2000 275 24 18447-18453 44 Castoria G Migliaccio A Bilancio A et al PI3-kinase in concert with Src promotes the S-phase entry of estradiolstimulated MCF-7 cells J EMBO J 2001 20 21 6050-6059 45 Kahlert S Nuedling S van Eickels M et al Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway J J Biol Chem 2000 275 24 18447-18453 46 Song R X Barnes C J Zhang Z et al The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane J Proc Natl Acad Sci U S A 2004 101 20 76-81 47 Song R X Zhang Z Santen R J A novel role of EGF and Shc in ER alpha membrane translocation and activation of MAPK in breast cancer cells 86th Annual Meeting of the Endocrine Society New Orleans USA Abstract 2004 4 74 48 Levin E R Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor J Mol Endocrinol 2003 17 3 309-317 49 Nahta R Yuan L X Zhang B et al Insulin-like growth factor- I receptor / human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells J Cancer Res 2005 65 23 11118-11128 50 Moore T Beltran L Carbajal S et al Energy balance modulates mouse skin tumor promotion through altered J Cancer Prev Res Phila 2012 5 10 1236-1246 51 p53 J Wu X G Peng S B Zhang N F et al Transcriptional regulation of p53 in multidrug resistant gene of breast cancer J Chin J Biochem Mol Biol 2012 28 2 152-157 52 Her-2 J Chai J Ma X Z Correlation between multi-drug resistance and Her 2 gene in breast cancer J Cancer Res Clinic 2012 24 4 232-234 53 PI3K /AKT J Guo C Y Ke W F Song K Y et al PI3K /AKT signaling pathway involves in the modulation of multi-drug resistance and metastasis in breast cancer J Prog Modern Biomed 2012 12 25 4809-4812