The investigator's recent studies have implicated the selective interaction of geldanamycin (GA) with certain cellular heat shock proteins in mediating anti-tumor activity, but the specific molecular consequences of this interaction in clinically relevant tumor models remain unclear. In this application, studies are proposed which will examine GA effects on the assembly and function of two heat shock protein-containing multimolecular complexes known to be important in the biology of many breast cancers; namely, the estrogen receptor (ER) and mutant p53. Reconstitution experiments using reticulocyte lysate will be used to identify the specific components of the ER and p53 complexes and assess drug effects on the dynamics of complex assembly. At the whole-cell level, GA effects on steady state-expression, subcellular localization and transcriptional transactivating activity of the two targets will be examined. Lastly, p53 and ER expression will be examined in breast tumor xenografts growing in SCID mice treated with GA. These experiments should define useful biologic endpoints for drug action in vivo and will allow assessment of the significance of the molecular effects observed in tissue culture for tumorigenicity in animals.
| Whitesell, L; Sutphin, P; An, W G et al. (1997) Geldanamycin-stimulated destabilization of mutated p53 is mediated by the proteasome in vivo. Oncogene 14:2809-16 |
| Whitesell, L; Cook, P (1996) Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells. Mol Endocrinol 10:705-12 |
