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Performing Data Mining And Integrative Analysis Of Biomarker in Breast Cancer Using Multiple Publicly Accessible Databases
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Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer

Marc A Becker1, Yasir H Ibrahim1, Annabell S Oh1

  • 1Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.

Plos One
|March 19, 2016
PubMed

Insights

Insulin-like growth factor-1 receptor (IGF-1R) therapies lack predictive biomarkers. Insulin receptor substrate (IRS) adaptor proteins are crucial for IGF-1R signaling in breast cancer, and IRS-specific gene signatures may predict anti-IGF therapy response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Targeting the type I insulin-like growth factor receptor (IGF-1R) is a potential cancer therapy strategy.
  • Predictive biomarkers for identifying tumors with activated IGF-1R are currently lacking.
  • Insulin receptor substrate (IRS) adaptor proteins link IGF-1R to downstream pathways essential for breast cancer malignancy.

Purpose of the Study:

  • To identify gene expression profiles downstream of IGF-1R and its adaptor proteins, IRS-1 and IRS-2.
  • To determine how IRS isoforms mediate IGF ligand-induced proliferation, motility, and gene expression.
  • To explore the potential of IRS-specific gene signatures as predictive biomarkers for anti-IGF therapies.

Main Methods:

  • Engineered IRS-null breast cancer cells (T47D-YA) to express IRS-1 or IRS-2.
  • Determined IGF ligand-induced proliferation, motility, and gene expression.
  • Derived global gene expression signatures (Early/Late IRS-1/2) and performed functional pathway analysis.
  • Investigated the role of TGFb2 in IGF-induced cell migration.
  • Analyzed the prognostic value of IRS proteins in different breast cancer subtypes.

Main Results:

  • IRS isoforms (IRS-1, IRS-2) mediated distinct gene expression profiles and functional pathways.
  • IRS-1/2 induced TGFb2 expression, and TGFb2 blockade abrogated IGF-induced cell migration.
  • IRS protein expression was a significant prognostic factor in the luminal B breast tumor subtype.
  • IRS adaptor signatures correlated with poor recurrence-free and overall survival.
  • IRS-specific gene signatures accurately reflect IGF activity.

Conclusions:

  • IRS adaptor protein expression is essential for IGF ligand responses in breast cancer cells.
  • IRS-specific gene signatures serve as effective surrogates for IGF activity.
  • These signatures hold potential for predicting patient response to anti-IGF therapies in breast cancer.

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