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 tum ors become refractory to current hormonal therapies within a year of starti ng treatment. To address this problem, we evaluated the effects of agents t hat 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-bindi ng protein itself and several essential molecular chaperones including Hsp9 0, We found that interaction of the Hsp90-binding drugs geldanamycin and ra dicicol 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 find ings, in vivo administration of the geldanamycin derivative 17-allylaminoge ldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both u terus and tumor. Drug administration also delayed the growth of established , hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 week s after the initiation of therapy. We conclude that in light of their novel mechanism of antihormone action, consideration should be given to examinin g the activity of 17AAG and other Hsp90-binding agents in patients with ref ractory breast cancer in future clinical trials, either alone or in combina tion with conventional hormone antagonists.