This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nielsen, T. O. Articles by Dunn, S. E. Search for Related Content PubMed PubMed Citation Articles by Nielsen, T. O. Articles by Dunn, S. E.

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

¹British Columbia Research Institute for Children’s and Women’s Health, Department of Pediatrics, Laboratory for Oncogenomic Research, University of British Columbia, Vancouver British Columbia, Canada; ²Genetic Pathology Evaluation Centre, Vancouver Hospital and Health Sciences Centre and British Columbia Cancer Agency, Vancouver British Columbia, Canada; ³Tumor Cell Biology Section, National Cancer Institute, Clinical Pharmacology Branch, National Cancer Institute, Bethesda, Maryland; and ⁴Department of Pediatrics, University of British Columbia, Canada

Urokinase plasminogen activator (uPA) expression in breast cancer is associated with relapse and a reduction in disease-specific survival. Thus, efforts are under way to identify uPA inhibitors. By screening a chemical library of >1000 compounds, 17-allyaminogeldanamycin (17AAG) was identified as a potent inhibitor of uPA by the National Cancer Institute and is now in Phase I clinical trials. At this time, it remains unclear how 17AAG blocks uPA; one possibility is through disruption of the insulin-like growth factor I receptor (IGF-IR) pathway. This would be consistent with studies from our laboratory showing that activation of IGF-IR results in the induction of uPA protein. In the study described herein, we observed that IGF-IR and uPA were highly expressed in 87 and 55% of breast cancer by screening tumor tissue microarrays representing 930 cases. A significant proportion (52.1% = 354 of 680 cases, P < 0.0001) of the patients had tumors expressing both proteins. uPA alone (P = 0.033) or in combination with IGF-IR (P = 0.0104) was indicative of decreased disease-specific survival. Next, we demonstrated that treating MDA-MB-231 cells with increasing concentrations of 17AAG resulted in IGF-IR degradation (IC₅₀ = 1.0 µM) and blocked signal transduction through the Akt and mitogen-activated protein kinase pathways. Finally, we found that 17AAG had a robust inhibitory effect on the production of uPA mRNAand protein in the presence of IGF-I. Thus, our study raises the possibility that 17AAG could prove to be an effective therapeutic agent for a large number of breast cancer patients by inhibiting the IGF-IR and ultimately uPA.

This article has been cited by other articles:

				T. Shimamura, D. Li, H. Ji, H. J. Haringsma, E. Liniker, C. L. Borgman, A. M. Lowell, Y. Minami, K. McNamara, S. A. Perera, et al. Hsp90 Inhibition Suppresses Mutant EGFR-T790M Signaling and Overcomes Kinase Inhibitor Resistance Cancer Res., July 15, 2008; 68(14): 5827 - 5838. [Abstract] [Full Text] [PDF]

				T. W. Bauer, F. Fan, W. Liu, E. R. Camp, A. Yang, R. J. Somcio, C. D. Bucana, R. Singh, and L. M. Ellis Targeting of Insulin-like Growth Factor-I Receptor with a Monoclonal Antibody Inhibits Growth of Hepatic Metastases from Human Colon Carcinoma in Mice Ann. Surg. Oncol., October 1, 2007; 14(10): 2838 - 2846. [Abstract] [Full Text] [PDF]

				W. Xu and L. Neckers Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells Clin. Cancer Res., March 15, 2007; 13(6): 1625 - 1629. [Full Text] [PDF]

				S.-H. Oh, O.-H. Lee, C. P. Schroeder, Y. W. Oh, S. Ke, H.-J. Cha, R.-W. Park, A. Onn, R. S. Herbst, C. Li, et al. Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition. Mol. Cancer Ther., November 1, 2006; 5(11): 2685 - 2695. [Abstract] [Full Text] [PDF]

				T. W. Bauer, R. J. Somcio, F. Fan, W. Liu, M. Johnson, D. P. Lesslie, D. B. Evans, G. E. Gallick, and L. M. Ellis Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells. Mol. Cancer Ther., July 1, 2006; 5(7): 1676 - 1682. [Abstract] [Full Text] [PDF]

				T. Takahashi, M. Ohmichi, J. Kawagoe, C. Ohshima, M. Doshida, T. Ohta, M. Saitoh, A. Mori-Abe, B. Du, H. Igarashi, et al. Growth Factors Change Nuclear Distribution of Estrogen Receptor-{alpha} via Mitogen-Activated Protein Kinase or Phosphatidylinositol 3-Kinase Cascade in a Human Breast Cancer Cell Line Endocrinology, September 1, 2005; 146(9): 4082 - 4089. [Abstract] [Full Text] [PDF]

				Y. Wang, J. Hailey, D. Williams, Y. Wang, P. Lipari, M. Malkowski, X. Wang, L. Xie, G. Li, D. Saha, et al. Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody Mol. Cancer Ther., August 1, 2005; 4(8): 1214 - 1221. [Abstract] [Full Text] [PDF]

				J. T. Price, J. M.W. Quinn, N. A. Sims, J. Vieusseux, K. Waldeck, S. E. Docherty, D. Myers, A. Nakamura, M. C. Waltham, M. T. Gillespie, et al. The Heat Shock Protein 90 Inhibitor, 17-Allylamino-17-demethoxygeldanamycin, Enhances Osteoclast Formation and Potentiates Bone Metastasis of a Human Breast Cancer Cell Line Cancer Res., June 1, 2005; 65(11): 4929 - 4938. [Abstract] [Full Text] [PDF]

				T. O. Nielsen, F. D. Hsu, K. Jensen, M. Cheang, G. Karaca, Z. Hu, T. Hernandez-Boussard, C. Livasy, D. Cowan, L. Dressler, et al. Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma Clin. Cancer Res., August 15, 2004; 10(16): 5367 - 5374. [Abstract] [Full Text] [PDF]