Aromatase is the enzyme that converts androgen to estrogen. An abnormal expression of aromatase in breast tissue is considered to be a risk factor for breast cancer. We previously demonstrated that ERα transfection and E2 treatment greatly enhanced the aromatase expression in SK-BR3 (ER-negative and aromatase-positive) and MCF-7 (ER-positive) breast cancer cells through a nongenomic fashion and cross-talk mechanism with growth- factor mediated pathways (Cancer Res., 63: 3546-3555, 2003). Recently, we initiated a study to examine the effect of the anticancer antibiotic geldanamycin (GA) on ER-regulated aromatase expression in breast cancer cells. This type of drugs has been identified for its ability to bind to Hsp90, and causes the destabilization and degradation of its client proteins, including ER, AR, and Her2. To examine the effect of GA on ER-regulated aromatase expression, we first treated ERα-overexpresing SK-BR3 cells with two GA analogs, 17-allylamino-17-demethoxygeldanamycin (17AAG) and 17-NN-dimethyl ethylene diamine-geldanamycin (17-DMAG), and found that the E2-induced aromatase activity was suppressed significantly by the treatment of these drugs in a dose-dependent manner, with an IC50 value of 25 nM. There was no potency difference observed between these two compounds. The observed reduction of ERα-induced aromatase activity by these two compounds resulted from the inhibition of the activity of promoter 1.1 of the aromatase gene as revealed by RT-PCR analysis using exon1s-specific RT-PCR analysis. Since SK-BR3 cells over-express Her-2/neu, and Her-2 can be degraded by 17-AAG, we decided to determine whether 17-AAG could inhibit the growth of SK-BR3 cells. As expected, the proliferation of SK-BR3 cells was markedly inhibited by the 17-AAG and 17-DMAG treatment. Results from this and other laboratories have showed that 17-AAG and 17-DMAG down regulates the activity/expression of critical proteins in breast carcinogenesis and can be a new therapeutic approach for the treatment of breast cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]