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Research Articles: Therapeutics, Targets, and Development

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

¹ Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois; ² Fox Chase Cancer Center, Philadelphia, Pennsylvania; and ³ Division of Biocomputing, University of New Mexico Health Sciences Center, Albuquerque, New Mexico

Requests for reprints: V. Craig Jordan, Alfred G. Knudson Chair of Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497. Phone: 215-728-7410; Fax: 215-728-7034. E-mail: v.craig.jordan{at}fccc.edu

Abstract

Aromatase inhibitors (AI) are being evaluated as long-term adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor (ER) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the non-aromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane down-regulated ER protein levels at high concentrations in a cell type–specific manner similarly as 17ß-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17ß-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ER. Molecular modeling also indicated that 17-hydroexemestane interacted with ER and AR through selective recognition motifs employed by 17ß-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs. [Mol Cancer Ther 2007;6(11):2817–27]

Grant support: Department of Defense Breast Program under award BC050277 Center of Excellence (V.C. Jordan; views and opinions of, and endorsements by the author(s) do not reflect those of the U.S. Army or the Department of Defense), Specialized Programs of Research Excellence in Breast Cancer CA89018 (V.C. Jordan), the Avon Foundation (V.C. Jordan), the Weg Fund (V.C. Jordan), and NIH P30 CA006927 (Fox Chase Cancer Center), an Eli Lilly Fellowship (Robert H. Lurie Comprehensive Cancer Center), the Lynn Sage Breast Cancer Research Foundation (Robert H. Lurie Comprehensive Cancer Center), the NIH Molecular Libraries Initiative award U54 MH074425-01, and by National Cancer Institute CA118100 (University of New Mexico Cancer Center).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 5/ 3/07; revised 8/28/07; accepted 10/ 1/07.