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Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Inhibitors of differentiation or DNA binding (Id) proteins have been shown to be involved in tumor growth, invasiveness, metastasis, and angiogenesis. Overexpression of Id proteins, especially Id1, correlates with unfavorable clinical prognosis. Thus, they are attractive molecular targets for anticancer therapy. Overexpression of Id proteins mediates breast cancer metastasis to lung. Targeting Id1 and Id3 expression in breast cancer cells reduces breast cancer metastasis in animal models. Different breast tumors failed to grow and/or metastasize in Id1 +/− Id3 −/− mice. Id1 and Id3 preferentially dimerize with the key regulatory E-proteins which inhibit the expression of different tumor suppressor genes. Nevertheless, the inhibition of tumorigenic activities of Id1 and Id3 at protein level has never been studied. Here, we isolated a novel peptide aptamer, Id1/3-PA7, specifically interacting with Id1 and Id3 from randomized combinatorial expression library using yeast and mammalian two-hybrid systems. Intracellular delivered Id1/3-PA7 co-localized to Id1 and Id3 and interfered with their functions. It repressed E47 protein sequestration by Id1 and Id3, activated the E-box promoter and increased the expression level of cyclin-dependent kinase inhibitors (CDKN1A and CDKN1B) in a dose-dependent fashion, paralleled by the cleavage of poly ADP ribose polymerase (PARP). These effects were counteracted by ectopically overexpressed Id1 and Id3. Peptide aptamer Id1/3-PA7 induced cell cycle arrest and apoptosis in breast cancer cells MCF7 and MDA-MB-231. In conclusion, Id1/3-PA7 could represent a nontoxic exogenous agent that can significantly provoke antiproliferative and apoptotic effects in breast cancer cells, which are associated with deregulated expression of Id1 and Id3.

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Acknowledgments

We thank R. Benezra (Sloan-Kettering Institute for Cancer Research, New York, USA) for providing plasmids pGL4.1-4Rtk-luc and pcDNA3-E47 and S. Schmitt (Core Facility Flow Cytometry, DKFZ), and S. Poppelreuter (Carl Zeiss MicroImaging GmbH) for supporting in cell cycle profiling and fluorescence microscopy. This study was supported by the Deutsche Forschungsgemeinschaft (grant HA3185/2-1and 2-3), the Helmholtz Society (grant VH-NG-213), the German Cancer Research Center and the Dietmar-Hopp Foundation.

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Authors and Affiliations

  1. Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany

    Demissew S. Mern & Barbara Burwinkel

  2. Molecular Therapy of Virus-Associated Cancers, German Cancer Research Center, Im Neuenheimer Feld 242, 69120, Heidelberg, Germany

    Karin Hoppe-Seyler & Felix Hoppe-Seyler

  3. Division of Hematology and Oncology, University of Freiburg Medical Center, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany

    Jens Hasskarl

  4. Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Voss Strasse 9, 69120, Heidelberg, Germany

    Barbara Burwinkel

Authors
  1. Demissew S. Mern
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  2. Karin Hoppe-Seyler
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  3. Felix Hoppe-Seyler
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  4. Jens Hasskarl
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Correspondence to Demissew S. Mern.

Additional information

Jens Hasskarl and Barbara Burwinkel equally contributed to this work.

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Mern, D.S., Hoppe-Seyler, K., Hoppe-Seyler, F. et al. Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells. Breast Cancer Res Treat 124, 623–633 (2010). https://doi.org/10.1007/s10549-010-0810-6

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  • DOI: https://doi.org/10.1007/s10549-010-0810-6

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