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

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Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
10:24

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins

Published on: September 28, 2012

M Z Lin1, K A Marzec1, J L Martin1

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

Oncogene
|November 27, 2012
PubMed

Insights

Insulin-like growth factor binding protein-3 (IGFBP-3) plays a key role in breast cancer cell DNA repair following chemotherapy. Targeting IGFBP-3 may sensitize tumors to DNA-damaging cancer therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • Epidermal growth factor receptor (EGFR) modulates DNA double-strand break (DSB) repair via DNA-dependent protein kinase catalytic subunit (DNA-PKcs) complexes.
  • Tumor resistance to DNA-damaging therapies is often linked to EGFR-mediated DSB repair mechanisms.
  • Insulin-like growth factor binding protein-3 (IGFBP-3) is a DNA-PKcs substrate and can transactivate EGFR.

Purpose of the Study:

  • To investigate the role of IGFBP-3 in the DNA damage response of breast cancer cells.
  • To determine if IGFBP-3 interacts with the EGFR-DNA-PK complex.
  • To explore IGFBP-3's function in breast cancer cell response to chemotherapeutic agents inducing DSBs.

Main Methods:

  • Utilized estrogen receptor-negative breast cancer cell lines (MDA-MB-468, Hs578T).
  • Administered cytotoxic drugs (etoposide, doxorubicin) and EGFR kinase inhibitor (gefitinib).
  • Performed co-immunoprecipitation, proximity ligation assay, and nonhomologous end-joining assays.
  • Conducted IGFBP-3 silencing experiments.

Main Results:

  • Cytotoxic drugs enhanced nuclear localization of EGFR and IGFBP-3, an effect reduced by gefitinib.
  • Enhanced association of IGFBP-3, EGFR, and DNA-PKcs was observed post-drug exposure.
  • IGFBP-3 silencing decreased DNA-PKcs activation, DNA repair, and EGFR-DNA-PKcs interaction.

Conclusions:

  • IGFBP-3 translocates to the nucleus and forms a complex with DNA-PKcs and EGFR in response to DNA damage.
  • IGFBP-3 plays an essential role in the DNA repair response to DNA-damaging therapy in breast cancer.
  • Targeting IGFBP-3's DNA repair function presents a potential therapeutic strategy for sensitizing breast cancer to chemo- or radiotherapy.

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