Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 3/2011

Open Access 01-06-2011 | Research article

Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes

Authors: Yinghui Zhang, Marja Moerkens, Sreenivasa Ramaiahgari, Hans de Bont, Leo Price, John Meerman, Bob van de Water

Published in: Breast Cancer Research | Issue 3/2011

Login to get access

Abstract

Introduction

Insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) is phosphorylated in all breast cancer subtypes. Past findings have shown that IGF-1R mediates antiestrogen resistance through cross-talk with estrogen receptor (ER) signaling and via its action upstream of the epidermal growth factor receptor and human epidermal growth factor receptor 2. Yet, the direct role of IGF-1R signaling itself in antiestrogen resistance remains obscure. In the present study, we sought to elucidate whether antiestrogen resistance is induced directly by IGF-1R signaling in response to its ligand IGF-1 stimulation.

Methods

A breast cancer cell line ectopically expressing human wild-type IGF-1R, MCF7/IGF-1R, was established by retroviral transduction and colony selection. Cellular antiestrogen sensitivity was evaluated under estrogen-depleted two-dimensional (2D) and 3D culture conditions. Functional activities of the key IGF-1R signaling components in antiestrogen resistance were assessed by specific kinase inhibitor compounds and small interfering RNA.

Results

Ectopic expression of IGF-1R in ER-positive MCF7 human breast cancer cells enhanced IGF-1R tyrosine kinase signaling in response to IGF-1 ligand stimulation. The elevated IGF-1R signaling rendered MCF7/IGF-1R cells highly resistant to the antiestrogens tamoxifen and fulvestrant. This antiestrogen-resistant phenotype involved mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B pathways downstream of the IGF-1R signaling hub and was independent of ER signaling. Intriguingly, a MAPK/ERK-dependent agonistic behavior of tamoxifen at low doses was triggered in the presence of IGF-1, showing a mild promitogenic effect and increasing ER transcriptional activity.

Conclusions

Our data provide evidence that the IGF-1/IGF-1R signaling axis may play a causal role in antiestrogen resistance of breast cancer cells, despite continuous suppression of ER transcriptional function by antiestrogens.
Appendix
Available only for authorised users
Literature
1.
Musgrove EA, Sutherland RL: Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009, 9: 631-643. 10.1038/nrc2713.PubMed
2.
Zilli M, Grassadonia A, Tinari N, Di Giacobbe A, Gildetti S, Giampietro J, Natoli C, Iacobelli S: Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer. Biochim Biophys Acta. 2009, 1795: 62-81.PubMed
3.
Tonini G, Schiavon G, Fratto ME, Vincenzi B, Santini D: Hormono-biological therapy in metastatic breast cancer: preclinical evidence, clinical studies and future directions. Expert Opin Biol Ther. 2008, 8: 221-234. 10.1517/14712598.8.2.221.PubMed
4.
Riggins RB, Schrecengost RS, Guerrero MS, Bouton AH: Pathways to tamoxifen resistance. Cancer Lett. 2007, 256: 1-24. 10.1016/j.canlet.2007.03.016.PubMedPubMedCentral
5.
Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, Rasmussen LM, Riese DJ, de Cremoux P, Stenvang J, Lykkesfeldt AE: Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 2009, 114: 263-275. 10.1007/s10549-008-0011-8.PubMed
6.
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: 217-233.PubMedPubMedCentral
7.
Dawood S, Cristofanilli M: Endocrine resistance in breast cancer: what really matters?. Ann Oncol. 2007, 18: 1289-1291. 10.1093/annonc/mdm359.PubMed
8.
Werner H, Bruchim I: The insulin-like growth factor-I receptor as an oncogene. Arch Physiol Biochem. 2009, 115: 58-71. 10.1080/13813450902783106.PubMed
9.
Surmacz E: Function of the IGF-I receptor in breast cancer. J Mammary Gland Biol Neoplasia. 2000, 5: 95-105. 10.1023/A:1009523501499.PubMed
10.
Sachdev D, Zhang X, Matise I, Gaillard-Kelly M, Yee D: The type I insulin-like growth factor receptor regulates cancer metastasis independently of primary tumor growth by promoting invasion and survival. Oncogene. 2010, 29: 251-262. 10.1038/onc.2009.316.PubMed
11.
Klinakis A, Szabolcs M, Chen G, Xuan S, Hibshoosh H, Efstratiadis A: Igf1r as a therapeutic target in a mouse model of basal-like breast cancer. Proc Natl Acad Sci USA. 2009, 106: 2359-2364. 10.1073/pnas.0810221106.PubMed
12.
Sachdev D, Hartell JS, Lee AV, Zhang X, Yee D: A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. J Biol Chem. 2004, 279: 5017-5024.PubMed
13.
Taunk NK, Goyal S, Moran MS, Yang Q, Parikh R, Haffty BG: Prognostic significance of IGF-1R expression in patients treated with breast-conserving surgery and radiation therapy. Radiother Oncol. 2010, 96: 204-208. 10.1016/j.radonc.2010.03.009.PubMed
14.
Ouban A, Muraca P, Yeatman T, Coppola D: Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol. 2003, 34: 803-808. 10.1016/S0046-8177(03)00291-0.PubMed
15.
Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, Park E, Gee JM, Finlay P, Jones HE, Nicholson RI, Carboni J, Gottardis M, Pollak M, Dunn SE: Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res. 2008, 68: 10238-10246. 10.1158/0008-5472.CAN-08-2755.PubMed
16.
Fagan DH, Yee D: Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2008, 13: 423-429. 10.1007/s10911-008-9098-0.PubMed
17.
Sisci D, Surmacz E: Crosstalk between IGF signaling and steroid hormone receptors in breast cancer. Curr Pharm Des. 2007, 13: 705-717. 10.2174/138161207780249182.PubMed
18.
Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R: Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res. 2008, 68: 826-833. 10.1158/0008-5472.CAN-07-2707.PubMed
19.
Knowlden JM, Hutcheson IR, Barrow D, Gee JM, Nicholson RI: Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology. 2005, 146: 4609-4618. 10.1210/en.2005-0247.PubMed
20.
Parisot JP, Hu XF, DeLuise M, Zalcberg JR: Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line. Br J Cancer. 1999, 79: 693-700. 10.1038/sj.bjc.6690112.PubMedPubMedCentral
21.
Song RX, Chen Y, Zhang Z, Bao Y, Yue W, Wang JP, Fan P, Santen RJ: Estrogen utilization of IGF-1-R and EGF-R to signal in breast cancer cells. J Steroid Biochem Mol Biol. 2010, 118: 219-230. 10.1016/j.jsbmb.2009.09.018.PubMed
22.
Santen RJ, Fan P, Zhang Z, Bao Y, Song RX, Yue W: Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. Steroids. 2009, 74: 586-594. 10.1016/j.steroids.2008.11.020.PubMed
23.
Huang X, Gao L, Wang S, McManaman JL, Thor AD, Yang X, Esteva FJ, Liu B: 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: 1204-1214. 10.1158/0008-5472.CAN-09-3321.PubMed
24.
Romano G, Prisco M, Zanocco-Marani T, Peruzzi F, Valentinis B, Baserga R: Dissociation between resistance to apoptosis and the transformed phenotype in IGF-I receptor signaling. J Cell Biochem. 1999, 72: 294-310. 10.1002/(SICI)1097-4644(19990201)72:2<294::AID-JCB14>3.0.CO;2-0.PubMed
25.
Swift S, Lorens J, Achacoso P, Nolan GP: Rapid production of retroviruses for efficient gene delivery to mammalian cells using 293T cell-based systems. Curr Protoc Immunol. 2001, Chapter 10: Unit 10.17C-PubMed
26.
Vichai V, Kirtikara K: Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006, 1: 1112-1116. 10.1038/nprot.2006.179.PubMed
27.
Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR: New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990, 82: 1107-1112. 10.1093/jnci/82.13.1107.
28.
Michalides R, Griekspoor A, Balkenende A, Verwoerd D, Janssen L, Jalink K, Floore A, Velds A, van't Veer L, Neefjes J: Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer. Cancer Cell. 2004, 5: 597-605. 10.1016/j.ccr.2004.05.016.PubMed
29.
Lopaczynski W, Terry C, Nissley P: Autophosphorylation of the insulin-like growth factor I receptor cytoplasmic domain. Biochem Biophys Res Commun. 2000, 279: 955-960. 10.1006/bbrc.2000.4046.PubMed
30.
Shelton JG, Steelman LS, White ER, McCubrey JA: Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. Cell Cycle. 2004, 3: 372-379.PubMed
31.
Vincent AM, Feldman EL: Control of cell survival by IGF signaling pathways. Growth Horm IGF Res. 2002, 12: 193-197. 10.1016/S1096-6374(02)00017-5.PubMed
32.
Sutherland RL, Green MD, Hall RE, Reddel RR, Taylor IW: Tamoxifen induces accumulation of MCF 7 human mammary carcinoma cells in the G0/G1 phase of the cell cycle. Eur J Cancer Clin Oncol. 1983, 19: 615-621. 10.1016/0277-5379(83)90177-3.PubMed
33.
Nicholson RI, Gee JMW, Francis AB, Manning DL, Wakeling AE, Katzenellenbogen BS: Observations arising from the use of pure antiestrogens on estrogen-responsive (Mcf-7) and estrogen growth-independent (K3) human breast-cancer cells. Endocr Relat Cancer. 1995, 2: 115-121. 10.1677/erc.0.0020115.
34.
Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL, Salisbury JD, Cheng AS, Li L, Abbosh PH, Huang TH, Nephew KP: Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res. 2006, 66: 11954-11966. 10.1158/0008-5472.CAN-06-1666.PubMed
35.
Hall JM, Korach KS: Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells. Mol Endocrinol. 2003, 17: 792-803. 10.1210/me.2002-0438.PubMed
36.
Litzenburger BC, Kim HJ, Kuiatse I, Carboni JM, Attar RM, Gottardis MM, Fairchild CR, Lee AV: BMS-536924 reverses IGF-IR-induced transformation of mammary epithelial cells and causes growth inhibition and polarization of MCF7 cells. Clin Cancer Res. 2009, 15: 226-237. 10.1158/1078-0432.CCR-08-0801.PubMedPubMedCentral
37.
Duncia JV, Santella JB 3rd, Higley CA, Pitts WJ, Wityak J, Frietze WE, Rankin FW, Sun JH, Earl RA, Tabaka AC, Teleha CA, Blom KF, Favata MF, Manos EJ, Daulerio AJ, Stradley DA, Horiuchi K, Copeland RA, Scherle PA, Trzaskos JM, Magolda RL, Trainor GL, Wexler RR, Hobbs FW, Olson RE: MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett. 1998, 8: 2839-2844. 10.1016/S0960-894X(98)00522-8.PubMed
38.
Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008, 68: 8022-8030. 10.1158/0008-5472.CAN-08-1385.PubMed
39.
Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM: The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res. 2008, 14: 6364-6370. 10.1158/1078-0432.CCR-07-4879.PubMed
40.
Arpino G, De Angelis C, Giuliano M, Giordano A, Falato C, De Laurentiis M, De Placido S: Molecular mechanism and clinical implications of endocrine therapy resistance in breast cancer. Oncology. 2009, 77 (Suppl 1): 23-37.PubMed
41.
Yue W, Fan P, Wang J, Li Y, Santen RJ: Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol. 2007, 106: 102-110. 10.1016/j.jsbmb.2007.05.008.PubMedPubMedCentral
42.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R: Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004, 96: 926-935. 10.1093/jnci/djh166.PubMed
43.
Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS: Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature. 2008, 456: 663-666. 10.1038/nature07483.PubMedPubMedCentral
44.
Green KA, Carroll JS: Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state. Nat Rev Cancer. 2007, 7: 713-722. 10.1038/nrc2211.PubMed
45.
Varma H, Conrad SE: Antiestrogen ICI 182,780 decreases proliferation of insulin-like growth factor I (IGF-I)-treated MCF-7 cells without inhibiting IGF-I signaling. Cancer Res. 2002, 62: 3985-3991.PubMed
46.
Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M: Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res. 1995, 55: 3331-3338.PubMed
47.
Surmacz E, Burgaud JL: Overexpression of insulin receptor substrate 1 (IRS-1) in the human breast cancer cell line MCF-7 induces loss of estrogen requirements for growth and transformation. Clin Cancer Res. 1995, 1: 1429-1436.PubMed
48.
Guvakova MA, Surmacz E: Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells. Exp Cell Res. 1997, 231: 149-162. 10.1006/excr.1996.3457.PubMed
49.
Bartucci M, Morelli C, Mauro L, Ando S, Surmacz E: Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. Cancer Res. 2001, 61: 6747-6754.PubMed
50.
Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998, 339: 1609-1618. 10.1056/NEJM199811263392207.PubMed
51.
Hodges LC, Cook JD, Lobenhofer EK, Li L, Bennett L, Bushel PR, Aldaz CM, Afshari CA, Walker CL: Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells. Mol Cancer Res. 2003, 1: 300-311.PubMed
52.
Ghayad SE, Vendrell JA, Larbi SB, Dumontet C, Bieche I, Cohen PA: Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways. Int J Cancer. 2010, 126: 545-562. 10.1002/ijc.24750.PubMed
53.
54.
Berstein LM: Molecular mechanisms of mutual effects of the pathological processes during combination of diabetes mellitus and cancer. Biochemistry (Mosc). 2003, 68: 703-706. 10.1023/A:1024630229195.
55.
Ignatov A, Ignatov T, Roessner A, Costa SD, Kalinski T: Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells. Breast Cancer Res Treat. 2010, 123: 87-96. 10.1007/s10549-009-0624-6.PubMed
56.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003, 4: 249-264. 10.1093/biostatistics/4.2.249.PubMed
57.
Wright GW, Simon RM: A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics. 2003, 19: 2448-2455. 10.1093/bioinformatics/btg345.PubMed
Metadata
Title
Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes
Authors
Yinghui Zhang
Marja Moerkens
Sreenivasa Ramaiahgari
Hans de Bont
Leo Price
John Meerman
Bob van de Water
Publication date
01-06-2011
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2011
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2883

Other articles of this Issue 3/2011

Breast Cancer Research 3/2011 Go to the issue

Review

Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition

Research article

NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications

Research article

Reversal of endocrine resistance in breast cancer: interrelationships among 14-3-3ζ, FOXM1, and a gene signature associated with mitosis

Research article

Impact of established prognostic factors and molecular subtype in very young breast cancer patients: pooled analysis of four EORTC randomized controlled trials

Research article

Optimal tumor sampling for immunostaining of biomarkers in breast carcinoma

Editorial

miR-200c at the nexus of epithelial-mesenchymal transition, resistance to apoptosis, and the breast cancer stem cell phenotype
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
Image Credits