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Basal-like breast cancer stem cells are sensitive to anti-DR5 mediated cytotoxicity

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Abstract

Breast cancer stem cells (BrCSC) are resistant to common therapeutic modalities including chemotherapy, radiation, and hormonal agents. They are thought to contribute to treatment resistance, relapse, and metastases. This study examines the effect of a monoclonal anti-DR5 antibody (TRA-8) and chemotherapy (adriamycin, taxol) on BrCSC populations from basal-like breast cancer cell lines. Doubly enriched BrCSC (CD44+, CD24−, ALDH+) cells were exposed to TRA-8 and control reagents and examined for cytotoxicity, caspase activation, tumorsphere formation and tumorigenicity. Doubly enriched BrCSC populations expressed cell surface DR5 and were sensitive to TRA-8 mediated cytotoxicity with induction of caspase 8 and 3 activation. TRA-8 at sub-nanomolar concentrations inhibited 2LMP and SUM159 BrCSC tumorsphere formation and was more than 50-fold more inhibitory than TRAIL or anti-DR4 at equimolar concentrations. Chemotherapy treatment of 2LMP and SUM159 cell lines resulted in a relative increase of BrCSC, whereas TRA-8 produced a decrease in the percentage of BrCSC. TRA-8 exposure to 2LMP and SUM159 BrCSC preparations produced significant inhibition of tumorigenicity. DR5 maybe a therapeutic target on the surface of basal-like BrCSC which is amenable to agonistic monoclonal anti-DR5 therapy.

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Acknowledgments

Supported in part by NIH SPORE in Breast Cancer 5P50 CA089019-08, Komen for the Cure Promise Grant KG090969, Breast Cancer Research Foundation of Alabama, and DOD Training grant W81XWH-11-1-0151. The authors thank Dr. William Grizzle for histologic analysis of tumor grafts. Technical support was provided by Andres Aristizabal and Enid Keyser. D. J. Buchsbaum and Albert F. LoBuglio: intellectual property interest in TRA-8, Daiichi Sankyo.

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Authors and Affiliations

  1. Department of Molecular and Cellular Pathology, University of Alabama at Birmingham, 1825 University Blvd. SHEL 771, Birmingham, AL, 35294-2182, USA

    Angelina I. Londoño-Joshi

  2. Department of Radiation Oncology, University of Alabama at Birmingham, 1825 University Blvd; SHEL 701, Birmingham, AL, 35294-2182, USA

    Patsy G. Oliver & Donald J. Buchsbaum

  3. Department of Medicine, University of Alabama at Birmingham Cancer Center, Birmingham, AL, USA

    Yufeng Li, Choo Hyung Lee, Andres Forero-Torres & Albert F. LoBuglio

Authors
  1. Angelina I. Londoño-Joshi
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  2. Patsy G. Oliver
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  3. Yufeng Li
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  4. Choo Hyung Lee
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  5. Andres Forero-Torres
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  6. Albert F. LoBuglio
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  7. Donald J. Buchsbaum
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Correspondence to Angelina I. Londoño-Joshi or Donald J. Buchsbaum.

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Londoño-Joshi, A.I., Oliver, P.G., Li, Y. et al. Basal-like breast cancer stem cells are sensitive to anti-DR5 mediated cytotoxicity. Breast Cancer Res Treat 133, 437–445 (2012). https://doi.org/10.1007/s10549-011-1763-0

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  • DOI: https://doi.org/10.1007/s10549-011-1763-0

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