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A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells

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Abstract

The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer.

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Abbreviations

BC:

Breast cancer

DMTI:

DNA methyltransferase inhibitor

EMT:

Epithelial-to-mesenchymal transition

FFPE:

Formalin-fixed paraffin-embedded

GF:

Growth factor

IHC:

Immunohistochemistry

Mfp:

Mammary fat pad

MMP:

Matrix metalloproteinase

PKC:

Protein kinase C

PKD:

Protein kinase D

RT:

Room temperature

TN:

Triple negative

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Acknowledgments

This work was supported by grants from the NIH (GM086435) and the Bankhead-Coley Program of the Florida Department of Health (1BG11). Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P50CA116201. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We also thank the Luther and Susie Harrison Foundation for their support, Irene K. Yan for technical assistance, and Alicia Fleming for help with the manuscript.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cancer Biology, Mayo Clinic, Griffin Building, Room 306, 4,500 San Pablo Road, Jacksonville, FL, 32224, USA

    Sahra Borges, Heike R. Döppler & Peter Storz

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  1. Sahra Borges
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  2. Heike R. Döppler
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  3. Peter Storz
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Correspondence to Peter Storz.

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Borges, S., Döppler, H.R. & Storz, P. A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells. Breast Cancer Res Treat 144, 79–91 (2014). https://doi.org/10.1007/s10549-014-2857-2

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  • DOI: https://doi.org/10.1007/s10549-014-2857-2

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