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IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation

Author

Listed:
  • Gerjon J. Ikink

    (The Netherlands Cancer Institute)

  • Mandy Boer

    (The Netherlands Cancer Institute)

  • Elvira R. M. Bakker

    (The Netherlands Cancer Institute)

  • John Hilkens

    (The Netherlands Cancer Institute)

Abstract

In search of oncogenic drivers and mechanisms affecting therapy resistance in breast cancer, we identified Irs4, a poorly studied member of the insulin receptor substrate (IRS) family, as a mammary oncogene by insertional mutagenesis. Whereas normally silent in the postnatal mammary gland, IRS4 is found to be highly expressed in a subset of breast cancers. We show that Irs4 expression in mammary epithelial cells induces constitutive PI3K/AKT pathway hyperactivation, insulin/IGF1-independent cell proliferation, anchorage-independent growth and in vivo tumorigenesis. The constitutive PI3K/AKT pathway hyperactivation by IRS4 is unique to the IRS family and we identify the lack of a SHP2-binding domain in IRS4 as the molecular basis of this feature. Finally, we show that IRS4 and ERBB2/HER2 synergistically induce tumorigenesis and that IRS4-expression confers resistance to HER2-targeted therapy. Taken together, our findings present the cellular and molecular mechanisms of IRS4-induced tumorigenesis and establish IRS4 as an oncogenic driver and biomarker for therapy resistance in breast cancer.

Suggested Citation

  • Gerjon J. Ikink & Mandy Boer & Elvira R. M. Bakker & John Hilkens, 2016. "IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13567
    DOI: 10.1038/ncomms13567
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    Cited by:

    1. András Zeke & Tamás Takács & Péter Sok & Krisztina Németh & Klára Kirsch & Péter Egri & Ádám Levente Póti & Isabel Bento & Gábor E. Tusnády & Attila Reményi, 2022. "Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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