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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2012

01-02-2012 | Preclinical Study

Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes

Authors: Rinat Yerushalmi, Karen A. Gelmon, Samuel Leung, Dongxia Gao, Maggie Cheang, Michael Pollak, Gulisa Turashvili, Blakes C. Gilks, Hagen Kennecke

Published in: Breast Cancer Research and Treatment | Issue 1/2012

Login to get access

Abstract

Insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal and malignant breast tissue and has been implicated in cell survival and resistance to cytotoxic therapies. We sought to assess the prognostic impact of IGF-1R expression among patients with early breast cancer and among breast cancer subtypes. Patients with stages I–III breast cancer with archival tumor tissue were included. Paraffin tissue blocks were used to construct a tissue microarray that was stained for ER, PR, Ki-67, HER2, EGFR, and cytokeratins 5/6 to classify the breast subgroups and for expression of IGF-1R, p27, and Bcl2 by immunohistochemistry. Kaplan–Meier plots were created by subtypes. Associations between IGF-1R and prognostic variables were examined in multivariate analysis. Among 2,871 eligible women the prognostic cut point for IGF-1R expression for breast-cancer-specific survival (BCSS) was Allred score <7 versus ≥7. IGF-1R was ≥7 in 52% (LuminalA), 57.5% (LuminalB), 44.8% (LuminalHER2), 9.7% HER2-enriched, and 22.5% (Basal-like), P = 1.3 × 10−52. IGF-1R+ was associated with age ≥50, lower histopathology grade, ER+, HER2 negativity (−), high p27 and high Bcl2 score. IGF-1R ≥7 was associated with better BCSS among LuminalB patients, hazard ratio = 0.64 (0.49–0.84); P = 1.2 × 10−3, and worse outcome in the HER2-enriched subtype, hazard ratio = 2.37 (1.21–4.64); P = 0.012. IGF-1R correlates with good prognostic markers among patients with early breast cancer and is differentially expressed with variable prognostic impact among breast cancer subtypes. Results may have relevance to the development of therapeutics targeting IGF-1R.
Appendix
Available only for authorised users
Literature
1.
Kasuya J, Paz IB, Maddux BA et al (1993) Characterization of human placental insulin-like growth factor-I/insulin hybrid receptors by protein microsequencing and purification. Biochemistry 32:13531–13536PubMedCrossRef
2.
Pandini G, Vigneri R, Costantino A et al (1999) Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res 5:1935–1944PubMed
3.
Adams TE, Epa VC, Garrett TP et al (2000) Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci 57:1050–1093PubMedCrossRef
4.
Shang Y, Mao Y, Batson J et al (2008) Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake. Mol Cancer Ther 7:2599–2608PubMedCrossRef
5.
Fagan DH, Yee D (2008) Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13:423–429PubMedCrossRef
6.
Werner H, Maor S (2006) The insulin-like growth factor-I receptor gene: a downstream target for oncogene and tumor suppressor action. Trends Endocrinol Metab 17:236–242PubMedCrossRef
7.
Ouban A, Muraca P, Yeatman T et al (2003) Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol 34:803–808PubMedCrossRef
8.
Law JH, Habibi G, Hu K et al (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68:10238–10246PubMedCrossRef
9.
Shimizu C, Hasegawa T, Tani Y et al (2004) Expression of insulin-like growth factor 1 receptor in primary breast cancer: immunohistochemical analysis. Hum Pathol 35:1537–1542PubMedCrossRef
10.
Railo MJ, von Smitten K, Pekonen F (1994) The prognostic value of insulin-like growth factor-I in breast cancer patients. Results of a follow-up study on 126 patients. Eur J Cancer 30A:307–311PubMedCrossRef
11.
Papa V, Gliozzo B, Clark GM et al (1993) Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Res 53:3736–3740PubMed
12.
Shin A, Ren Z, Shu XO et al (2007) Expression patterns of insulin-like growth factor 1 (IGF-I) and its receptor in mammary tissues and their associations with breast cancer survival. Breast Cancer Res Treat 105:55–61PubMedCrossRef
13.
Bonneterre J, Peyrat JP, Beuscart R et al (1990) Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer. Cancer Res 50:6931–6935PubMed
14.
Gualberto A, Pollak M (2009) Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28:3009–3021PubMedCrossRef
15.
Blum G, Gazit A, Levitzki A (2000) Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry 39:15705–15712PubMedCrossRef
16.
Garcia-Echeverria C, Pearson MA, Marti A et al (2004) In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5:231–239PubMedCrossRef
17.
Mitsiades CS, Mitsiades NS, McMullan CJ et al (2004) Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 5:221–230PubMedCrossRef
18.
Yuen JS, Macaulay VM (2008) Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Expert Opin Ther Targets 12:589–603PubMedCrossRef
19.
Stephen RL, Shaw LE, Larsen C et al (2001) Insulin-like growth factor receptor levels are regulated by cell density and by long term estrogen deprivation in MCF7 human breast cancer cells. J Biol Chem 276:40080–40086PubMedCrossRef
20.
Sachdev D, Singh R, Fujita-Yamaguchi Y et al (2006) Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implications for anti-insulin-like growth factor therapy in breast cancer. Cancer Res 66:2391–2402PubMedCrossRef
21.
Burtrum D, Zhu Z, Lu D et al (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63:8912–8921PubMed
22.
Pandini G, Wurch T, Akla B et al (2007) Functional responses and in vivo anti-tumour activity of h7C10: A humanised monoclonal antibody with neutralising activity against the insulin-like growth factor-1 (IGF-1) receptor and insulin/IGF-1 hybrid receptors. Eur J Cancer 43:1318–1327PubMedCrossRef
23.
Sachdev D, Drug evaluation (2007) CP-751871, a human antibody against type I insulin-like growth factor receptor for the potential treatment of cancer. Curr Opin Mol Ther 9:299–304PubMed
24.
Jin Q, Esteva FJ (2008) Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia 13:485–498PubMedCrossRef
25.
Schillaci R, Salatino M, Cassataro J et al (2006) Immunization with murine breast cancer cells treated with antisense oligodeoxynucleotides to type I insulin-like growth factor receptor induced an antitumoral effect mediated by a CD8+ response involving Fas/Fas ligand cytotoxic pathway. J Immunol 176:3426–3437PubMed
26.
Capodanno A, Camerini A, Orlandini C et al (2009) Dysregulated PI3 K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma. Hum Pathol 40:1408–1417PubMedCrossRef
27.
Charpin C, Giusiano S, Secq V et al (2009) Quantitative immunocytochemical profile to predict early outcome of disease in triple-negative breast carcinomas. Int J Oncol 34:983–993PubMedCrossRef
28.
Vendrell JA, Robertson KE, Ravel P et al (2008) A candidate molecular signature associated with tamoxifen failure in primary breast cancer. Breast Cancer Res 10:R88PubMedCrossRef
29.
Bremer TM, Jacquemier J, Charafe-Jauffret E et al (2009) Prognostic marker profile to assess risk in stage I-III hormone receptor-positive breast cancer patients. Int J Cancer 124:896–904PubMedCrossRef
30.
Fleming ID, Cooper JS, Henson DE et al (1997) AJCC Cancer Staging Manual, 5th edn. Lippincott-Raven, Philadelphia
31.
Bearhs OH, Henson DE, Hutter RVP et al (1992) AJCC Cancer Staging Manual, 5th edn. Lippincott-Raven, Philadelphia
32.
Cheang MC, Treaba DO, Speers CH et al (2006) Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 24:5637–5644PubMedCrossRef
33.
Voduc D, Cheang M, Nielsen T (2008) GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol Biomarkers Prev 17:365–373PubMedCrossRef
34.
Mulligan AM, O’Malley FP, Ennis M et al (2007) Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat 106:39–47PubMedCrossRef
35.
Hakam A, Fang Q, Karl R et al (2003) Coexpression of IGF-1R and c-src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci 48:1972–1978PubMedCrossRef
36.
Power KA, Chen JM, Saarinen NM et al (2008) Changes in biomarkers of estrogen receptor and growth factor signaling pathways in MCF-7 tumors after short- and long-term treatment with soy and flaxseed. J Steroid Biochem Mol Biol 112:13–19PubMedCrossRef
37.
Harvey JM, Clark GM, Osborne CK et al (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481PubMed
38.
Cheang MC, Chia SK, Voduc D et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750PubMedCrossRef
39.
Cheang MC, Voduc D, Bajdik C et al (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14:1368–1376PubMedCrossRef
40.
Nielson TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374CrossRef
41.
Rajput AB, Turbin DA, Cheang MC et al (2008) Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4, 444 cases. Breast Cancer Res Treat 107:249–257PubMedCrossRef
42.
Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:7252–7259PubMedCrossRef
43.
Govindarajulu US, Malloy EJ, Gangali B et al. (2009) The comparison of alternative smoothing methods for fitting non-linear exposure-response relationships with cox models in a simulation study. Int J Biostat 5. doi: 10.​2202/​1557-4679.​1104
44.
McShane LM, Altman DG, Sauerbei W et al (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072PubMedCrossRef
45.
Hayes DF, Ethier S, Lippman ME (2006) New guidelines for reporting of tumor marker studies in breast cancer research and treatment: REMARK. Breast Cancer Res Treat 100:237–238PubMedCrossRef
46.
Robert A, Toupance B, Tremblay M et al (2009) Impact of inbreeding on fertility in a pre-industrial population. Eur J Hum Genet 17:673–681PubMedCrossRef
47.
Creighton CJ, Fu X, Hennessy BT et al (2010) Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res 12:R40. doi:101186/​bcr2594 PubMedCrossRef
48.
Creighton CJ, Casa A, Lazard Z et al (2008) Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26:4078–4085PubMedCrossRef
49.
Chu IM, Hengst L, Slingerland JM (2008) The cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8:253–267PubMedCrossRef
50.
Esparis-Ogando A, Ocana A, Rodriguez-Barrueco R et al (2008) Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-overexpressing breast cancer cells. Ann Oncol 19:1860–1869PubMedCrossRef
51.
Binder C, Marx D, Overhoff R et al (1995) Bcl-2 protein expression in breast cancer in relation to established prognostic factors and other clinicopathological variables. Ann Oncol 6:1005–1010PubMed
52.
Joensuu H, Pylkkanen L, Toikkanen S (1994) Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198PubMed
53.
Lee KH, Im SA, Oh DY et al (2007) Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy. BMC Cancer 7:63PubMedCrossRef
54.
Haluska P, Carboni JM, TenEyck C et al (2008) HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther 7:2589–2598PubMedCrossRef
55.
Chakraborty AK, Welsh A, Digiovanna MP (2010) Co-targeting the insulin-like growth factor I receptor enhances growth-inhibitory and pro-apoptotic effects of anti-estrogens in human breast cancer cell lines. Breast Cancer Res Treat 120:327–335PubMedCrossRef
56.
Weroha SJ, Haluska P (2008) IGF-1 receptor inhibitors in clinical trials—early lessons. J Mammary Gland Biol Neoplasia 13:471–483PubMedCrossRef
57.
Guix M, Faber AC, Wang SE et al (2008) Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118:2609–2619PubMed
58.
Camirand A, Lu Y, Pollak M (2002) Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med Sci Monit 8:BR521-6PubMed
59.
Jones HE, Goddard L, Gee JM et al (2004) Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814PubMedCrossRef
60.
Nahta R, Yuan LX, Zhang B et al (2005) Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 65:11118–11128PubMedCrossRef
61.
Lu Y, Zi X, Zhao Y et al (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (herceptin). J Natl Cancer Inst 93:1852–1857PubMedCrossRef
62.
Kaufman PA, Ferrero JM, Bourgeois H et al (2010) A randomized, double-blind, placebo-controlled, phase 2 study of AMG-479 with Exemestane (E) or Fulvestrant (F) in postmenopausal women with hormone receptor positive (HR+) metastatic (M) or locally advanced (LA) breast cancer. In: San Antonio breast cancer symposium, CTRC-AACR, San-Antonio, Texas, December 2010
63.
Pitts TM, Tan AK, Kulikowski GN et al (2010) Development of an integrated genomic classifier for novel agent in colorectal cancer: approach to individualized therapy in early development. Clin Cancer Res 16:3193–3204PubMedCrossRef
64.
Metadata
Title
Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes
Authors
Rinat Yerushalmi
Karen A. Gelmon
Samuel Leung
Dongxia Gao
Maggie Cheang
Michael Pollak
Gulisa Turashvili
Blakes C. Gilks
Hagen Kennecke
Publication date
01-02-2012
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-011-1529-8

Other articles of this Issue 1/2012

Breast Cancer Research and Treatment 1/2012 Go to the issue

Preclinical Study

Prognostic value of acquired uniparental disomy (aUPD) in primary breast cancer

Epidemiology

Correlation of white female breast cancer incidence trends with nitrogen dioxide emission levels and motor vehicle density patterns

Clinical trial

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II–IIIc breast cancer

Preclinical Study

Detection of aberrant promoter methylation of GSTP1, RASSF1A, and RARβ2 in serum DNA of patients with breast cancer by a newly established one-step methylation-specific PCR assay

Preclinical study

ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells

Preclinical study

Prolonged mammosphere culture of MCF-7 cells induces an EMT and repression of the estrogen receptor by microRNAs
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