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Research Articles: Therapeutics, Targets, and Development

Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression

¹ Cancer Research-UK Labs, Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus; ² Department of Chemistry, University College London, Christopher Ingold Laboratories, London, United Kingdom

Requests for reprints: Eric W-F. Lam, Cancer Research-UK Labs, Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-5829; Fax: 44-20-8383-5830. E-mail: eric.lam{at}imperial.ac.uk

Abstract

Elevated expression or activity of the transcription factor forkhead box M1 (FOXM1) is associated with the development and progression of many malignancies, including breast cancer. In this study, we show that the thiazole antibiotic thiostrepton selectively induces cell cycle arrest and cell death in breast cancer cells through down-regulating FOXM1 expression. Crucially, our data show that thiostrepton treatment reduced FOXM1 expression in a time- and dose-dependent manner, independent of de novo protein synthesis and predominantly at transcriptional and gene promoter levels. Our results indicate that thiostrepton can induce cell death through caspase-dependent intrinsic and extrinsic apoptotic pathways as well as through caspase-independent death mechanisms, as observed in MCF-7 cells, which are deficient of caspase-3 and caspase-7. Cell cycle analysis showed that thiostrepton induced cell cycle arrest at G₁ and S phases and cell death, concomitant with FOXM1 repression in breast cancer cells. Furthermore, thiostrepton also shows efficacy in repressing breast cancer cell migration, metastasis, and transformation, which are all downstream functional attributes of FOXM1. We also show that overexpression of a constitutively active FOXM1 mutant, N-FOXM1, can abrogate the antiproliferative effects of thiostrepton. Interestingly, thiostrepton has no affect on FOXM1 expression and proliferation of the untransformed MCF-10A breast epithelial cells. Collectively, our data show that FOXM1 is one of the primary cellular targets of thiostrepton in breast cancer cells and that thiostrepton may represent a novel lead compound for targeted therapy of breast cancer with minimal toxicity against noncancer cells. [Mol Cancer Ther 2008;7(7):2022–32]

Grant support: Medical Research Council (J.M-M. Kwok and E.W-F. Lam), Cancer Research UK (S.S. Myatt, R.C. Coombes, and E.W-F. Lam), and Office of Science and Innovation, Department of Trade and Industry, United Kingdom (D. Constantinidou, R.C. Coombes, and E.W-F. Lam).

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.

Received 2/25/08; accepted 4/ 2/08.