Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.
Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer. Unstimulated estrogen and progesterone receptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90. We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of anti-hormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.
Bagatell
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Department of Pediatrics, Steele Memorial Children's Research Center, University of Arizona, Tucson, Arizona 85724, USA. bagatell@peds.arizona.edu
Khan
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Paine-Murrieta
G
G
Taylor
C W
CW
Akinaga
S
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Whitesell
L
L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004967:Estrogens / Q000627:therapeutic use; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011485:Protein Binding; D011809:Quinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004967:Estrogens; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D011809:Quinones; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; C001277:geldanamycin