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

• Published in: Nature communications 2016-11, Vol.7 (1), p.13567-15, Article 13567
• Main Authors: Ikink, Gerjon J., Boer, Mandy, Bakker, Elvira R. M., Hilkens, John
• Format: Article
• Language: English
• Subjects: 13/106; 13/95; 38/47; 38/89; 42/70; 631/208/68; 631/67/1347; 64/60; 692/4028/67/395; 82/1; Animals; Antineoplastic Agents - pharmacology; Breast cancer; Cell growth; Cell Proliferation; Cells, Cultured; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Humanities and Social Sciences; Humans; Insulin; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Kinases; Mammary Tumor Virus, Mouse - physiology; Mice; Mice, Inbred BALB C; multidisciplinary; Mutagenesis; Neoplasms, Experimental; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Science; Science (multidisciplinary); Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13567

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. IRS proteins are scaffolds that can activate survival signalling pathways. In this study, the authors identified IRS4 as a potential oncogene in breast cancer that leads to the constitutive activation of PI3K/AKT signalling and thus confers resistance to HER2-targeted therapy.