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Selective activity of deguelin identifies therapeutic targets for androgen receptor-positive breast cancer

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Abstract

Triple-negative breast cancers (TNBC) are aggressive malignancies with no effective targeted therapies. Recent gene expression profiling of these heterogeneous cancers and the classification of cell line models now allows for the identification of compounds with selective activities against molecular subtypes of TNBC. The natural product deguelin was found to have selective activity against MDA-MB-453 and SUM-185PE cell lines, which both model the luminal androgen receptor (LAR) subtype of TNBC. Deguelin potently inhibited proliferation of these cells with GI50 values of 30 and 61 nM, in MDA-MB-453 and SUM-185PE cells, respectively. Deguelin had exceptionally high selectivity, 197 to 566-fold, for these cell lines compared to cell lines representing other TNBC subtypes. Deguelin’s mechanisms of action were investigated to determine how it produced these potent and selective effects. Our results show that deguelin has dual activities, inhibiting PI3K/Akt/mTOR signaling, and decreasing androgen receptor levels and nuclear localization. Based on these data, we hypothesized that the combination of the mTOR inhibitor rapamycin and the antiandrogen enzalutamide would have efficacy in LAR models. Rapamycin and enzalutamide showed additive effects in MDA-MB-453 cells, and both drugs had potent antitumor efficacy in a LAR xenograft model. These results suggest that the combination of antiandrogens and mTOR inhibitors might be an effective strategy for the treatment of androgen receptor-expressing TNBC.

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Acknowledgments

This study was funded by grants to S.L.M. and R.H.C. from the National Cancer Institute (UO1CA182740), the UTHSCSA President’s Council Excellence Award (S.L.M), and the Greehey Distinguished Chair in Targeted Molecular Therapeutics endowment (S.L.M.). Support of the Flow Cytometry, Macromolecular Structure and Mass Spectrometry Shared Resources of the CTRC Cancer Center Support Grant (P30 CA054174) are gratefully acknowledged. A.J.R was partially supported by the IMSD program of the NIGMS (1R25GM095480-01). The authors would like to thank the San Antonio Botanical Gardens for allowing us to collect samples of Amorpha fruticosa used in this study. We thank Dr. April Risinger for her thoughtful review of the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Andrew J. Robles & Susan L. Mooberry

  2. Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Susan L. Mooberry

  3. Natural Product Discovery Group, Institute for Natural Products Applications and Research Technologies, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA

    Shengxin Cai & Robert H. Cichewicz

  4. Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA

    Shengxin Cai & Robert H. Cichewicz

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  1. Andrew J. Robles
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Correspondence to Robert H. Cichewicz or Susan L. Mooberry.

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Robles, A.J., Cai, S., Cichewicz, R.H. et al. Selective activity of deguelin identifies therapeutic targets for androgen receptor-positive breast cancer. Breast Cancer Res Treat 157, 475–488 (2016). https://doi.org/10.1007/s10549-016-3841-9

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