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Letter

The role of insulin-like growth factor-I receptor in the development of Herceptin resistance

Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Ozden Altundag

Houston, Texas

Paolo Morandi

Department of Medical Oncology, S. Bortolo General Hospital, Vicenza, Italy

Bulent Ozcakar

Department of Chest Disease, Fatih University Faculty of Medicine, Ankara, Turkey

Cem Boruban

Department of Medical Oncology, Selcuk University Faculty of Medicine, Konya, Turkey

To the Editor: We read with great interest the article by Tanner et al. regarding development of a novel cell line established from patient with Herceptin-resistant breast cancer (1). They showed that lack of growth inhibition was rationalized by the unaltered Akt phosphorylation in these resistant JIMT-1 cells. They discuss different Herceptin resistance mechanisms that may develop in these cells. We want to comment on another resistance mechanism. The insulin-like growth factor-I receptor (IGF-IR) initiates a strong proliferative and antiapoptotic signal (2). Binding of IGF-I to IGF-IR results in autophosphorylation of the receptor, leading to recruitment and phosphorylation of Src homology and collagen and IRS-1 adaptor protein. This action of IGF-IR results in activation of the Ras/Raf/mitogen-activated protein kinase pathway and/or the phosphatidylinositol 3-kinase pathway, which influence cell proliferation and survival (3, 4). Lu et al. (5, 6) showed that in breast cancer cell models that overexpress HER-2, an increased level of IGF-IR signaling seems to interfere with the action of trastuzumab by reducing p27 (Kip1) protein level by increased degradation. Therefore, strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab. Further clinical studies are warranted to support these preclinical results.

References

1. Tanner M, Kapanen AI, Junttila T, et al. Characterization of a novel cell line established from a patient with Herceptin-resistant breast cancer. Mol Cancer Ther 2004;3:1585–92.[Abstract/Free Full Text]
2. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000;92:1472–89.[Abstract/Free Full Text]
3. Porter AC, Vaillancourt RR. Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene 1998;17:1343–52.[CrossRef][Medline]
4. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.[CrossRef][Medline]
5. Lu Y, Zi X, Zhao Y, et al. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001;93:1852–7.[Abstract/Free Full Text]
6. Lu Y, Zi X, Pollak M. Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer 2004;108:334–41.[CrossRef][Medline]

University of Tempere, Institute of Medical Technology, Tempere, Finland

In Response:

The main goal of our report (1) was to characterize the newly established cell line JIMT-1, which could be a useful tool to study Herceptin resistance mechanism(s) in vitro and in xenograft-bearing immunodeficient mice. To keep the text short, we did not want to speculate on possible resistance mechanisms that we have not studied with JIMT-1 cells thus far. A detailed review on possible Herceptin resistance mechanisms was referred to in the article (2).

It is my pleasure to accept the authors' view that insulin-like growth factor-I receptor signaling could well be one of the mechanisms behind constitutively active phosphatidylinositol 3-kinase and Herceptin resistance. We have recently made the JIMT-1 cell line available for the research community via an international cell collection.¹ The role of insulin-like growth factor-I receptor signaling and many other possible resistance mechanisms can then be directly tested with JIMT-1 cells, which is the first patient-derived in vitro model of breast cancer derived from a clinically Herceptin-resistant patient.

Footnotes

¹ www.dsmz.de

References

1. Tanner M, Kapanen A, Junttila T, et al. Characterization of a novel cell line established from a Herceptin-resistant breast cancer patient. Mol Cancer Ther 2004;3:1585–92.
2. Cardoso F, Piccart MJ, Durbecq V, Di Leo A. Resistance to trastuzumab: a necessary evil or a temporary challenge? Clin Breast Cancer 2002;3:247–57.[Medline]

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