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Inhibition of SDF-1/CXCR4-induced epithelial–mesenchymal transition by kisspeptin-10

  • Preclinical study
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Abstract

Recently we have shown that breast cancer cell invasion was dramatically increased when co-cultured with MG63 cells. In addition we have generated mesenchymal transformed MCF-7 breast cancer cells (MCF-7-EMT), showing significantly increased invasion in contrast to wild type MCF-7 cells (MCF-7 WT). In this study we have analyzed whether stromal derived factor-1 (SDF-1) is responsible for MCF-7 and T-47-D breast cancer cell invasion and epithelial–mesenchymal-transition (EMT). In addition we have analyzed whether kisspeptin-10 (KP-10) treatment affects SDF-1-induced invasion and EMT. Invasion was quantified by assessment of MCF-7 and T-47-D breast cancer cell migration rate through an artificial basement membrane in a modified Boyden chamber during co-culture with MG63 cells or after treatment with SDF-1α, SDF-1β or the combination of both isoforms. Induction of EMT was verified by analysis of protein expression of epithelial marker E-cadherin (CDH1) and mesenchymal markers N-cadherin (CDH2) and Vimentin (VIM). The role of SDF-1 for invasion and induction of EMT in breast cancer cells was analyzed by blocking SDF-1 secretion during co-culture with MG63 cells. In addition effects of KP-10 treatment on SDF-1-induced invasion and EMT were analyzed. Breast cancer cell invasion was significantly increased when co-cultured with MG63 cells. During co-culture SDF-1 protein expression of MG63 cells was significantly induced. The increased breast cancer cell invasion could be blocked by anti-SDF-1 antibodies. Treatment of breast cancer cells in monoculture (without MG63) with SDF-1α, SDF-1β or the combination of both isoforms resulted in a significant escalation of breast cancer cell invasion and induction of EMT. Protein expression of mesenchymal markers CDH2 and VIM was clearly elevated, whereas protein expression of epithelial marker CDH1 was clearly decreased. The SDF-1-induced increase of cell invasion was significantly reduced after treatment with KP-10. In addition, induction of EMT was inhibited. Furthermore, protein expression of the binding site of SDF-1, CXC-motive-chemokine receptor 4 (CXCR-4), was reduced by KP-10. Treatment of MCF-7-EMT cells with KP-10 resulted in a significant drop of cell invasion and CXCR-4 protein expression. Our findings suggest that SDF-1 plays a major role in breast cancer invasion and EMT. SDF-1-induced invasion and EMT can be inhibited by KP-10 treatment by down-regulating CXCR-4 expression.

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Acknowledgments

Grant support: Deutsche Krebshilfe—Dr. Mildred Scheel Stiftung. We thank Sonja Blume for excellent technical assistance.

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The authors declare that they have no conflict interests.

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, 37075, Göttingen, Germany

    Carsten Gründker, Gerd Bauerschmitz, Juliane Knapp, Elena Schmidt, Theresa Olbrich & Günter Emons

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  1. Carsten Gründker
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  2. Gerd Bauerschmitz
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  3. Juliane Knapp
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  4. Elena Schmidt
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  5. Theresa Olbrich
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Correspondence to Carsten Gründker.

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Gründker, C., Bauerschmitz, G., Knapp, J. et al. Inhibition of SDF-1/CXCR4-induced epithelial–mesenchymal transition by kisspeptin-10. Breast Cancer Res Treat 152, 41–50 (2015). https://doi.org/10.1007/s10549-015-3463-7

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  • DOI: https://doi.org/10.1007/s10549-015-3463-7

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