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IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive

Gerjon J Ikink1, Mandy Boer1, Elvira R M Bakker1

  • 1Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, CX 1066 Amsterdam, The Netherlands.

Nature Communications
|November 24, 2016
PubMed

Insights

Researchers discovered Insulin Receptor Substrate 4 (IRS4) as a new breast cancer oncogene. IRS4 drives tumor growth and resistance to HER2-targeted therapies by activating the PI3K/AKT pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Breast cancer remains a leading cause of mortality, with ongoing research focused on identifying novel oncogenic drivers and understanding mechanisms of therapeutic resistance.
  • The insulin receptor substrate (IRS) family plays critical roles in cellular signaling pathways, but the specific function of IRS4 in cancer, particularly breast cancer, is not well understood.

Purpose of the Study:

  • To identify novel oncogenic drivers in breast cancer.
  • To elucidate the mechanisms by which IRS4 contributes to tumorigenesis and therapy resistance.
  • To investigate the role of IRS4 in the context of ERBB2/HER2 signaling.

Main Methods:

  • Insertional mutagenesis in a mouse model to identify oncogenes.
  • Analysis of IRS4 expression in human breast cancer samples.
  • In vitro studies using mammary epithelial cells to assess the functional consequences of IRS4 expression.
  • Investigation of downstream signaling pathways, including PI3K/AKT.
  • Studies on the synergistic effects of IRS4 and ERBB2/HER2.
  • Assessment of resistance to HER2-targeted therapy in IRS4-expressing cells.

Main Results:

  • Irs4 was identified as a mammary oncogene through insertional mutagenesis.
  • IRS4 is normally silent in the postnatal mammary gland but highly expressed in a subset of breast cancers.
  • IRS4 expression induces constitutive PI3K/AKT pathway hyperactivation, leading to insulin/IGF1-independent proliferation, anchorage-independent growth, and in vivo tumorigenesis.
  • The unique constitutive PI3K/AKT activation by IRS4 is attributed to the lack of a SHP2-binding domain.
  • IRS4 synergizes with ERBB2/HER2 to promote tumorigenesis and confers resistance to HER2-targeted therapy.

Conclusions:

  • IRS4 acts as a potent oncogenic driver in breast cancer.
  • The molecular mechanism involves constitutive PI3K/AKT pathway hyperactivation due to the absence of a SHP2-binding domain.
  • IRS4 is a potential biomarker for predicting resistance to HER2-targeted therapies.
  • Targeting IRS4 may offer new therapeutic strategies for breast cancer patients, particularly those with HER2-positive disease.

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