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 Beliakoff, J. Articles by Whitesell, L. Search for Related Content PubMed PubMed Citation Articles by Beliakoff, J. Articles by Whitesell, L.

Hormone-Refractory Breast Cancer Remains Sensitive to the Antitumor Activity of Heat Shock Protein 90 Inhibitors

Steele Memorial Children’s Research Center [J. B., R. B., L. W.] and Arizona Cancer Center [G. P-M., C. W. T.], University of Arizona, Tucson, Arizona 85724, and Department of Tumor Endocrinology, Institute of Cancer Biology, The Danish Cancer Society, Copenhagen, Denmark [A. E. L.]

Purpose: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore, we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting the function of Hsp90.

Experimental Design: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts.

Results: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1. Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear, but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex.

Conclusions: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.

This article has been cited by other articles:

				X. Long, M. Fan, R. M. Bigsby, and K. P. Nephew Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-{alpha}-dependent and estrogen receptor-{alpha}-independent mechanisms Mol. Cancer Ther., July 1, 2008; 7(7): 2096 - 2108. [Abstract] [Full Text] [PDF]

				X. Pi and C. Patterson Twin Layers of Lightning: A New Role for the Chaperone Hsp90 in Angiogenesis Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 6 - 7. [Full Text] [PDF]

				S. Chandarlapaty, A. Sawai, Q. Ye, A. Scott, M. Silinski, K. Huang, P. Fadden, J. Partdrige, S. Hall, P. Steed, et al. SNX2112, a Synthetic Heat Shock Protein 90 Inhibitor, Has Potent Antitumor Activity against HER Kinase Dependent Cancers Clin. Cancer Res., January 1, 2008; 14(1): 240 - 248. [Abstract] [Full Text] [PDF]

				B. J. Weigel, S. M. Blaney, J. M. Reid, S. L. Safgren, R. Bagatell, J. Kersey, J. P. Neglia, S. P. Ivy, A. M. Ingle, L. Whitesell, et al. A Phase I Study of 17-Allylaminogeldanamycin in Relapsed/Refractory Pediatric Patients with Solid Tumors: A Children's Oncology Group Study Clin. Cancer Res., March 15, 2007; 13(6): 1789 - 1793. [Abstract] [Full Text] [PDF]

				K. Lehnes, A. D. Winder, C. Alfonso, N. Kasid, M. Simoneaux, H. Summe, E. Morgan, M. C. Iann, J. Duncan, M. Eagan, et al. The Effect of Estradiol on in Vivo Tumorigenesis Is Modulated by the Human Epidermal Growth Factor Receptor 2/Phosphatidylinositol 3-Kinase/Akt1 Pathway Endocrinology, March 1, 2007; 148(3): 1171 - 1180. [Abstract] [Full Text] [PDF]

				E. Oxelmark, J. M. Roth, P. C. Brooks, S. E. Braunstein, R. J. Schneider, and M. J. Garabedian The Cochaperone p23 Differentially Regulates Estrogen Receptor Target Genes and Promotes Tumor Cell Adhesion and Invasion. Mol. Cell. Biol., July 1, 2006; 26(14): 5205 - 5213. [Abstract] [Full Text] [PDF]

				L. Lipfert, J. E. Fisher, N. Wei, A. Scafonas, Q. Su, J. Yudkovitz, F. Chen, S. Warrier, E. T. Birzin, S. Kim, et al. Antagonist-Induced, Activation Function-2-Independent Estrogen Receptor {alpha} Phosphorylation Mol. Endocrinol., March 1, 2006; 20(3): 516 - 533. [Abstract] [Full Text] [PDF]

				T Frogne, J S Jepsen, S S Larsen, C K Fog, B L Brockdorff, and A E Lykkesfeldt Antiestrogen-resistant human breast cancer cells require activated Protein Kinase B/Akt for growth Endocr. Relat. Cancer, September 1, 2005; 12(3): 599 - 614. [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]

				R I Nicholson, C Staka, F Boyns, I R Hutcheson, and J M W Gee Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy Endocr. Relat. Cancer, December 1, 2004; 11(4): 623 - 641. [Abstract] [Full Text] [PDF]

				J. Sun and J. K. Liao Induction of Angiogenesis by Heat Shock Protein 90 Mediated by Protein Kinase Akt and Endothelial Nitric Oxide Synthase Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2238 - 2244. [Abstract] [Full Text] [PDF]

				R. Bagatell and L. Whitesell Altered Hsp90 function in cancer: A unique therapeutic opportunity Mol. Cancer Ther., August 1, 2004; 3(8): 1021 - 1030. [Abstract] [Full Text] [PDF]