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The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells

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Abstract

Although ErbB receptors have been implicated in prostate cancer progression, ErbB-directed drugs have not proven effective for prostate cancer treatment. The ErbB3-binding protein EBP1 affects both ErbB2 and androgen receptor signaling, two components of the response to ErbB-targeted therapies. We therefore examined the effects of EBP1 expression on the response to the ErbB1/2 tyrosine kinase inhibitor lapatinib. We found a negative correlation between endogenous EBP1 levels and lapatinib sensitivity in prostate cancer cell lines. We then overexpressed or inhibited expression of EBP1. Silencing EBP1 expression increased lapatinib sensitivity and overexpression of EBP1 increased resistance in androgen-containing media. Androgen depletion resulted in an increased sensitivity of androgen-dependent EBP1 expressing cells to lapatinib, but did not affect the lapatinib sensitivity of hormone resistant cells. However, EBP1 silenced cells were still more sensitive to lapatinib than EBP1-expressing cells in the absence of androgens. The increase in sensitivity to lapatinib following EBP1 silencing was associated with increased ErbB2 levels. In addition, lapatinib treatment increased ErbB2 levels in sensitive cells that express low levels of EBP1, but decreased ErbB2 levels in resistant EBP1-expressing cells. In contrast, ErbB3 and phospho ErbB3 levels were not affected by either changes in EBP1 levels or lapatinib treatment. The production of the ErbB3/4 ligand heregulin was increased in EBP1-silenced cells. EBP1-induced changes in AR levels were not associated with changes in lapatinib sensitivity. These studies suggest that the ability of EBP1 to activate ErbB2 signaling pathways results in increased lapatinib sensitivity.

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Acknowledgments

This work was supported by NIH Grant 1R01CA138583 (AWH). We thank Dr. M. Lin (University of Nebraska Medical Center) for permission to use the C81 cells and Dr. Yun Qiu (University of Maryland School of Medicine) for providing these cells.

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Authors and Affiliations

  1. Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, Baltimore, MD, 21201, USA

    Smita Awasthi, Heather Ezelle, Bret A. Hassel & Anne W. Hamburger

  2. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA

    Smita Awasthi & Anne W. Hamburger

  3. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA

    Heather Ezelle & Bret A. Hassel

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  1. Smita Awasthi
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  2. Heather Ezelle
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Correspondence to Anne W. Hamburger.

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Awasthi, S., Ezelle, H., Hassel, B.A. et al. The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells. Mol Cell Biochem 405, 177–186 (2015). https://doi.org/10.1007/s11010-015-2409-z

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  • DOI: https://doi.org/10.1007/s11010-015-2409-z

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