J Breast Cancer.  2014 Jun;17(2):113-120.

Positive Expression of Insulin-Like Growth Factor-1 Receptor Is Associated with a Positive Hormone Receptor Status and a Favorable Prognosis in Breast Cancer

• Shin SJ
• Gong G
• Lee HJ
• Kang J
• Bae YK
• Lee A
• Cho EY
• Lee JS
• Suh KS
• Lee DW
• Jung WH

Abstract

PURPOSE
Insulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined.
METHODS
IGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive.
RESULTS
Positive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031).
CONCLUSION
Positive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status.

Keyword

Breast neoplasms; Insulin-like growth factor 1 receptor; Immunohistochemistry

MeSH Terms

Breast
Breast Neoplasms*
Disease-Free Survival
Humans
Immunohistochemistry
Multivariate Analysis
Phenobarbital
Prognosis*
Receptor, Epidermal Growth Factor
Survival Rate
Phenobarbital
Receptor, Epidermal Growth Factor

Figure

• 

  Figure 1 Immunohistochemical staining of insulin-like growth factor 1 receptor (IGF-1R). IGF-1R expression was scored according to the intensity of the membrane staining in accordance with human epidermal growth factor receptor 2 expression scoring system described in the Hercep Test™ manual (Dako). (A) Score=0, (B) score=1, (C) score=2, (D) score=3 (Immunohistochemical staining, ×100).

• 

  Figure 2 Kaplan-Meier analysis of (A) overall survival (OS) and (B) disease-free survival (DFS) in breast cancer. IGF-1R=insulin-like growth factor 1 receptor.

• 

  Figure 3 Kaplan-Meier analysis of overall survival (OS) and disease-free survival (DFS) in breast cancer subtypes: luminal A (A and B), luminal B (C and D), HER2 (E and F), and triple-negative subtypes (G and H). IGF-1R=insulin-like growth factor 1 receptor.

Reference

1. Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME, et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res. 1990; 50:48–53.

2. LeRoith D, Roberts CT Jr. The insulin-like growth factor system and cancer. Cancer Lett. 2003; 195:127–137.

3. Nielsen TO, Andrews HN, Cheang M, Kucab JE, Hsu FD, Ragaz J, et al. Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res. 2004; 64:286–291.

4. Jin Q, Esteva FJ. 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. 2008; 13:485–498.

5. Pegram MD, Pietras R, Bajamonde A, Klein P, Fyfe G. Targeted therapy: wave of the future. J Clin Oncol. 2005; 23:1776–1781.

6. Zhang H, Yee D. The therapeutic potential of agents targeting the type I insulin-like growth factor receptor. Expert Opin Investig Drugs. 2004; 13:1569–1577.

7. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst. 2001; 93:1852–1857.

8. Nahta R. Deciphering the role of insulin-like growth factor-I receptor in trastuzumab resistance. Chemother Res Pract. 2012; 2012:648965.

9. 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. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000; 406:747–752.

11. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003; 100:8418–8423.

12. van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415:530–536.

13. Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, et al. 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.

14. Yerushalmi R, Gelmon KA, Leung S, Gao D, Cheang M, Pollak M, et al. Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes. Breast Cancer Res Treat. 2012; 132:131–142.

15. Robbins P, Pinder S, de Klerk N, Dawkins H, Harvey J, Sterrett G, et al. Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol. 1995; 26:873–879.

16. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403-410. Histopathology. 2002; 41(3A):151–152.

17. Bae YK, Gong G, Kang J, Lee A, Cho EY, Lee JS, et al. HER2 status by standardized immunohistochemistry and silver-enhanced in situ hybridization in Korean breast cancer. J Breast Cancer. 2012; 15:381–387.

18. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007; 25:118–145.

19. Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol. 2005; 23:7350–7360.

20. Bonneterre J, Peyrat JP, Beuscart R, Demaille A. Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer. Cancer Res. 1990; 50:6931–6935.

21. Papa V, Gliozzo B, Clark GM, McGuire WL, Moore D, Fujita-Yamaguchi Y, et al. Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Res. 1993; 53:3736–3740.

22. Shin A, Ren Z, Shu XO, Cai Q, Gao YT, Zheng W. 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. 2007; 105:55–61.

23. Gallardo A, Lerma E, Escuin D, Tibau A, Muñoz J, Ojeda B, et al. 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. 2012; 106:1367–1373.

24. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011; 121:2750–2767.

25. Chakraborty AK, Liang K, DiGiovanna MP. Co-targeting insulin-like growth factor I receptor and HER2: dramatic effects of HER2 inhibitors on nonoverexpressing breast cancer. Cancer Res. 2008; 68:1538–1545.