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Aromatase Destabilizer: Novel Action of Exemestane, a Food and Drug Administration–Approved Aromatase Inhibitor

Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California

Requests for reprints: Shiuan Chen, Department of Surgical Research, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-359-8111, ext. 63454; Fax: 626-301-8972; E-mail: schen{at}coh.org.

Using Western blot as the major technique, we studied the effects of the three Food and Drug Administration (FDA)–approved aromatase inhibitors (AI) on aromatase protein stability in the aromatase-overexpressing breast cancer cell line MCF-7aro. We have found that exemestane treatment significantly reduces aromatase protein level. Exemestane induces aromatase degradation in a dose-responsive manner (25-200 nmol/L), and the effect can be seen in as early as 2 hours. Metabolic labeling with S³⁵-methionine was used to determine the half-life (t_1/2) of aromatase protein. In the presence of 200 nmol/L exemestane, the t_1/2 of aromatase was reduced to 12.5 hours from 28.2 hours in the untreated cells. Furthermore, exemestane-induced aromatase degradation can be completely blocked by 10 µmol/L MG132, indicating that the degradation is mediated by proteasome. We also examined the effect of exemestane on aromatase mRNA level using real-time reverse transcription-PCR. No significant changes in mRNA level were detected after 8 hours of treatment with exemestane (200 nmol/L). This is the first report on the evaluation of three FDA-approved AIs on the stability of the aromatase protein. We have found that exemestane, different from letrozole and anastrozole, can destabilize the aromatase protein. (Cancer Res 2006; 66(21): 10281-6)

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