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Interaction between nuclear insulin receptor substrate-2 and NF-κB in IGF-1 induces response in breast cancer cells

Shufang Wu1, Bo Zhou, Lin Xu

  • 1Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710060, PR China. shufangw@hotmail.com

Oncology Reports
|November 3, 2010
PubMed

Insights

Insulin receptor substrate-2 (IRS-2) plays a key role in breast cancer progression. This study shows IRS-2 activates NF-κB via the PI3K/Akt pathway, promoting cancer cell growth and cyclin D1 transcription.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell signaling

Background:

  • Insulin receptor substrate-1 (IRS-1) and IRS-2 share homology but have distinct roles in breast cancer.
  • Previous research has primarily focused on IRS-1, with limited understanding of IRS-2's function.
  • Distinct functions of IRS-1 and IRS-2 in breast cancer progression are increasingly recognized.

Purpose of the Study:

  • To elucidate the specific role of IRS-2 in breast cancer cell proliferation and signaling pathways.
  • To investigate the involvement of IRS-2 in insulin-like growth factor-1 (IGF-1) induced responses.
  • To explore the interaction between IRS-2, NF-κB, and cyclin D1 in breast cancer cells.

Main Methods:

  • Antisense strategies to deplete endogenous IRS-2 in MCF-7 and BT-20 breast cancer cells.
  • Assessment of cell proliferation following serum withdrawal.
  • Analysis of PI3K/Akt and NF-κB activation pathways.
  • Investigation of IGF-1 induced responses, including nuclear translocation.
  • Chromatin immunoprecipitation to determine nuclear IRS-2 recruitment to the cyclin D1 promoter.

Main Results:

  • Depletion of IRS-2 impaired cell proliferation and blunted PI3K/Akt and NF-κB activation in response to IGF-1.
  • IGF-1 promoted nuclear translocation of IRS-2 and NF-κB in breast cancer cells.
  • Nuclear IRS-2 interaction with NF-κB-p65 and PI3K binding tyrosine residues were crucial for NF-κB activity.
  • Nuclear IRS-2 was recruited to the cyclin D1 promoter, an event dependent on NF-κB-p65.
  • Selective inhibition of NF-κB-p65 abolished IRS-2 occupancy at the cyclin D1 promoter.

Conclusions:

  • IRS-2 significantly contributes to IGF-1-induced responses in breast cancer cells, partly by activating NF-κB through the PI3K/Akt pathway.
  • The crosstalk between nuclear IRS-2 and NF-κB is implicated in the transcriptional progression of breast cancer cells.
  • Targeting the IRS-2/NF-κB pathway may offer a novel therapeutic strategy for breast cancer.

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