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Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance

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Abstract

Post-extravasation survival is a key rate-limiting step of metastasis; however, not much is known about the factors that enable survival of the metastatic cancer cell at the secondary site. Furthermore, metastatic nodules are often refractory to current therapies, necessitating the elucidation of molecular changes that affect the chemosensitivity of metastases. Drug resistance exhibited by tumor spheroids has been shown to be mediated by cell adhesion and can be abrogated by addition of E-cadherin blocking antibody. We have previously shown that hepatocyte coculture induces the re-expression of E-cadherin in breast and prostate cancer cells. In this study, we show that this E-cadherin re-expression confers a survival advantage, particularly in the liver microenvironment. E-cadherin re-expression in MDA-MB-231 breast cancer cells resulted in increased attachment to hepatocytes. This heterotypic adhesion between cancer cells and secondary organ parenchymal cells activated ERK MAP kinase, suggesting a functional pro-survival role for E-cadherin during metastatic colonization of the liver. In addition, breast cancer cells that re-expressed E-cadherin in hepatocyte coculture were more chemoresistant compared to 231-shEcad cells unable to re-express E-cadherin. Similar results were obtained in DU-145 prostate cancer cells induced to re-express E-cadherin in hepatocyte coculture or following chemical induction by the GnRH agonist buserelin or the EGFR inhibitor PD153035. These results suggest that E-cadherin re-expression and other molecular changes imparted by a partial mesenchymal to epithelial reverting transition at the secondary site increase post-extravasation survival of the metastatic cancer cell and may help to elucidate why chemotherapy commonly fails to treat metastatic breast cancer.

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Abbreviations

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial to mesenchymal transition

GnRH agonist:

Gonadotropin-releasing hormone agonist

MErT:

Mesenchymal to epithelial reverting transition

PI-3k:

Phospho-Inositide-3OH kinase

shRNA:

Short hairpin RNA

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Acknowledgments

These studies were supported by a Merit Award from the Veterans Administration and an IDEA Award from the Department of Defense (USA) CDMRP in Breast Cancer. We thank members of the Wells laboratory for discussions and suggestions.

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Authors and Affiliations

  1. Department of Pathology, Pittsburgh VAMC and University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Yvonne Chao, Qian Wu, Christopher Shepard & Alan Wells

  2. University of Pittsburgh School of Medicine, 3550 Terrace Street, S713 Scaife Hall, Pittsburgh, PA, 15261, USA

    Alan Wells

Authors
  1. Yvonne Chao
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  2. Qian Wu
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  3. Christopher Shepard
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  4. Alan Wells
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Corresponding author

Correspondence to Alan Wells.

Additional information

Yvonne Chao and Qian Wu contributed equivalently to this work.

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Chao, Y., Wu, Q., Shepard, C. et al. Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. Clin Exp Metastasis 29, 39–50 (2012). https://doi.org/10.1007/s10585-011-9427-3

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  • DOI: https://doi.org/10.1007/s10585-011-9427-3

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