A new therapeutic strategy against hormone-dependent breast cancer: the preclinical development of a dual aromatase and sulfatase inhibitor

Foster, Paul A. and Chander, S.K. and Newman, Simon P. and Woo, L.W. Lawrence and Sutcliffe, O.B. and Bubert, C. and Zhou, Dujin and Chen, Shiuan and Potter, B.V.L. and Reed, M.J. and Purohit, A. (2008) A new therapeutic strategy against hormone-dependent breast cancer: the preclinical development of a dual aromatase and sulfatase inhibitor. Clinical Cancer Research, 14. pp. 6469-6477. ISSN 1557-3265 (http://dx.doi.org/10.1158/1078-0432.CCR-08-1027)

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Abstract

The production of E2 is paramount for the growth of estrogen receptor-positive breast cancer. Various strategies have been used, including the use of enzyme inhibitors against either aromatase (AROM) or steroid sulfatase (STS), in an attempt to ablate E2 levels. Both these enzymes play a critical role in the formation of estrogenic steroids and their inhibitors are now showing success in the clinic. We show here, in a xenograft nude mouse model, that the inhibition of both enzymes using STX681, a dual AROM and STS inhibitor (DASI), is a potential new therapeutic strategy against HDBC. MCF-7 cells stably expressing either AROM cDNA (MCF-7AROM) or STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of either androstenedione (A4) or E2 sulfate and bearing either MCF-7AROM or MCF-7STS tumors were orally treated with STX64, letrozole, or STX681. Treatment was administered for 28 days. Mice were weighed and tumor measurements were taken weekly. STX64, a potent STS inhibitor, completely blocked MCF-7STS tumor growth but failed to attenuate MCF-7AROM tumor growth. In contrast, letrozole inhibited MCF-7AROM tumors but had no effect on MCF-7STS tumors. STX681 completely inhibited the growth of both tumors. AROM and STS activity was also completely inhibited by STX681, which was accompanied by a significant reduction in plasma E2 levels. This study indicates that targeting both the AROM and the STS enzyme with a DASI inhibits HDBC growth and is therefore a potentially novel treatment for this malignancy.

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