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 Price, J. T. Articles by Thompson, E. W. Search for Related Content PubMed PubMed Citation Articles by Price, J. T. Articles by Thompson, E. W.

The Heat Shock Protein 90 Inhibitor, 17-Allylamino-17-demethoxygeldanamycin, Enhances Osteoclast Formation and Potentiates Bone Metastasis of a Human Breast Cancer Cell Line

¹ Tumour Cell Migration and Metastasis Laboratory, ² Bone Joint and Cancer Laboratory, ³ Pharmacogenomics Laboratory, and ⁴ Victorian Breast Cancer Research Consortium Invasion and Metastasis Laboratory, St. Vincent's Institute; and Departments of ⁵ Medicine, ⁶ Physiology, and ⁷ Surgery, University of Melbourne, Melbourne, Australia

Requests for reprints: John Price, Tumour Cell Migration and Metastasis Laboratory, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, 3065 Melbourne, Victoria, Australia. Phone: 61-3-9288-2480; Fax: 61-3-9416-2676; E-mail: jprice{at}svi.edu.au.

Breast cancer metastasis to the bone occurs frequently, causing numerous complications including severe pain, fracture, hypercalcemia, and paralysis. Despite its prevalence and severity, few effective therapies exist. To address this, we examined whether the heat shock protein 90 (Hsp90) inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), would be efficacious in inhibiting breast cancer metastasis to bone. Utilizing the human breast cancer subline, MDA-MB-231SA, previously in vivo selected for its enhanced ability to generate osteolytic bone lesions, we determined that 17-AAG potently inhibited its in vitro proliferation and migration. Moreover, 17-AAG significantly reduced MDA-MB-231SA tumor growth in the mammary-fat pad of nude mice. Despite these findings, 17-AAG enhanced the incidence of bone metastasis and osteolytic lesions following intracardiac inoculation in the nude mouse. Consistent with these findings, 17-AAG enhanced osteoclast formation 2- to 4-fold in mouse bone marrow/osteoblast cocultures, receptor activator of nuclear factor B ligand (RANKL)–stimulated bone marrow, and RAW264.7 cell models of in vitro osteoclastogenesis. Moreover, the drug enhanced osteoclastogenesis in human cord blood progenitor cells, demonstrating that its effects were not limited to mouse models. In addition to 17-AAG, other Hsp90 inhibitors, such as radicicol and herbimycin A, also enhanced osteoclastogenesis. A pro-osteolytic action of 17-AAG independent of tumor presence was also determined in vivo, in which 17-AAG–treated tumor-naïve mice had reduced trabecular bone volume with an associated increase in osteoclast number. Thus, HSP90 inhibitors can stimulate osteoclast formation, which may underlie the increased incidence of osteolysis and skeletal tumor incidence caused by 17-AAG in vivo. These data suggest an important contraindication to the Hsp90 targeted cancer therapy currently undergoing clinical trial.

This article has been cited by other articles:

				C. MOSER, S. A. LANG, and O. STOELTZING Heat-shock Protein 90 (Hsp90) as a Molecular Target for Therapy of Gastrointestinal Cancer Anticancer Res, June 1, 2009; 29(6): 2031 - 2042. [Abstract] [Full Text] [PDF]

				J. Schwock, N. Dhani, M. P.-J. Cao, J. Zheng, R. Clarkson, N. Radulovich, R. Navab, L.-C. Horn, and D. W. Hedley Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts Cancer Res., June 1, 2009; 69(11): 4750 - 4759. [Abstract] [Full Text] [PDF]

				F. KOGA, K. KIHARA, and L. NECKERS Inhibition of Cancer Invasion and Metastasis by Targeting the Molecular Chaperone Heat-shock Protein 90 Anticancer Res, March 1, 2009; 29(3): 797 - 807. [Abstract] [Full Text] [PDF]

				R. E. Coleman, T. A. Guise, A. Lipton, G. D. Roodman, J. R. Berenson, J.-J. Body, B. F. Boyce, L. M. Calvi, P. Hadji, E. V. McCloskey, et al. Advancing Treatment for Metastatic Bone Cancer: Consensus Recommendations from the Second Cambridge Conference Clin. Cancer Res., October 15, 2008; 14(20): 6387 - 6395. [Abstract] [Full Text] [PDF]

				A. Yano, S. Tsutsumi, S. Soga, M.-J. Lee, J. Trepel, H. Osada, and L. Neckers Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone PNAS, October 7, 2008; 105(40): 15541 - 15546. [Abstract] [Full Text] [PDF]

				S. A. Eccles, A. Massey, F. I. Raynaud, S. Y. Sharp, G. Box, M. Valenti, L. Patterson, A. de Haven Brandon, S. Gowan, F. Boxall, et al. NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis Cancer Res., April 15, 2008; 68(8): 2850 - 2860. [Abstract] [Full Text] [PDF]

				C. Moser, S. A. Lang, S. Kainz, A. Gaumann, S. Fichtner-Feigl, G. E. Koehl, H. J. Schlitt, E. K. Geissler, and O. Stoeltzing Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo Mol. Cancer Ther., November 1, 2007; 6(11): 2868 - 2878. [Abstract] [Full Text] [PDF]

				S. A. Lang, C. Moser, A. Gaumann, D. Klein, G. Glockzin, F. C. Popp, M. H. Dahlke, P. Piso, H. J. Schlitt, E. K. Geissler, et al. Targeting Heat Shock Protein 90 in Pancreatic Cancer Impairs Insulin-like Growth Factor-I Receptor Signaling, Disrupts an Interleukin-6/Signal-Transducer and Activator of Transcription 3/Hypoxia-Inducible Factor-1{alpha} Autocrine Loop, and Reduces Orthotopic Tumor Growth Clin. Cancer Res., November 1, 2007; 13(21): 6459 - 6468. [Abstract] [Full Text] [PDF]

				Y. Zheng, H. Zhou, J. R.K. Modzelewski, R. Kalak, J. M. Blair, M. J. Seibel, and C. R. Dunstan Accelerated Bone Resorption, Due to Dietary Calcium Deficiency, Promotes Breast Cancer Tumor Growth in Bone Cancer Res., October 1, 2007; 67(19): 9542 - 9548. [Abstract] [Full Text] [PDF]

				D. Stellas, A. Karameris, and E. Patsavoudi Monoclonal Antibody 4C5 Immunostains Human Melanomas and Inhibits Melanoma Cell Invasion and Metastasis Clin. Cancer Res., March 15, 2007; 13(6): 1831 - 1838. [Abstract] [Full Text] [PDF]

				S. A. Lang, D. Klein, C. Moser, A. Gaumann, G. Glockzin, M. H. Dahlke, W. Dietmaier, U. Bolder, H. J. Schlitt, E. K. Geissler, et al. Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo Mol. Cancer Ther., March 1, 2007; 6(3): 1123 - 1132. [Abstract] [Full Text] [PDF]

				F. Koga, W. Xu, T. S. Karpova, J. G. McNally, R. Baron, and L. Neckers Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation PNAS, July 25, 2006; 103(30): 11318 - 11322. [Abstract] [Full Text] [PDF]