Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibioti c that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation. 17-AAG causes a retinoblastoma (RE)-dependent G, block in cancer cells and is now in clinical trial. In breast cancer cells, G, block is accompanied by diffe rentiation and followed by apoptosis. The differentiation is characterized by specific changes in morphology and induction of milk fat proteins and li pid droplets. In cells lacking RE, neither G, arrest nor differentiation oc curs; instead, they undergo apoptosis in mitosis. Introduction of RE into t hese cells restores the differentiation response to 17-AAG. Inhibitors of t he ras, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways cause accumulation of milk fat proteins and induction of lipid dr oplets when associated with GI arrest but do not cause morphological change s. Thus, regulation of Hsp90 function by 17-AAG in breast cancer cells indu ces RE-dependent morphological and functional mammary differentiation. G, a rrest is sufficient for some hut not all aspects of the phenotype. Inductio n of differentiation may be responsible for some of the antitumor effects o f this drug.