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The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents

Oncogene volume 33, pages 85–96 (2014)Cite this article

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Abstract

Following exposure to radiation and chemotherapeutic agents, the epidermal growth factor receptor (EGFR) can modulate the repair of DNA double-strand breaks (DSB) by forming protein complexes that include the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). This is one of the key mechanism by which tumors become resistant to DNA-damaging therapies. Our previous studies have shown that insulin-like growth factor binding protein-3 (IGFBP-3) is a substrate for DNA-PKcs, and can transactivate EGFR. We therefore questioned whether IGFBP-3 might interact with the EGFR−DNA-PK complex that regulates the DNA damage response. The aim of this study was to delineate the role of IGFBP-3 in the response of breast cancer cells to DSB-inducing chemotherapeutic agents. In the estrogen receptor-negative breast cancer cell lines MDA-MB-468 and Hs578T, which express IGFBP-3 highly, nuclear localization of EGFR and IGFBP-3 was enhanced by treatment with cytotoxic drugs etoposide or doxorubicin and reduced by the EGFR kinase inhibitor gefitinib. Enhanced association among IGFBP-3, EGFR and DNA-PKcs, following the exposure to DNA-damaging drugs was supported by both co-immunoprecipitation analysis and direct visualization by proximity ligation assay. The activation of DNA-PKcs at Ser2056, DNA repair as measured by a nonhomologous end-joining assay, and the increase in EGFR and DNA-PKcs interaction induced by DNA-damaging agents, were all decreased by IGFBP-3 silencing, suggesting that IGFBP-3 has an obligatory role in the DNA repair response to DNA-damaging therapy. In conclusion, IGFBP-3 co-translocation to the nucleus of breast cancer cells and its formation of a complex with DNA-PKcs and EGFR in response to DNA damage shows its potential involvement in the regulation of DNA repair. This suggests the possibility of a therapeutic approach for sensitizing breast cancer to chemo- or radiotherapy by targeting the DNA repair function of IGFBP-3.

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Article 23 September 2019

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Acknowledgements

This work was supported by Grant Number DP0984232 to RCB from the Australian Research Council.

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  1. Hormones and Cancer Division, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, Australia

    M Z Lin, K A Marzec, J L Martin & R C Baxter

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Correspondence to R C Baxter.

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Lin, M., Marzec, K., Martin, J. et al. The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents. Oncogene 33, 85–96 (2014). https://doi.org/10.1038/onc.2012.538

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