Title |
IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation
|
---|---|
Published in |
Nature Communications, November 2016
|
DOI | 10.1038/ncomms13567 |
Pubmed ID | |
Authors |
Gerjon J. Ikink, Mandy Boer, Elvira R. M. Bakker, John Hilkens |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | 33% |
United States | 1 | 33% |
Unknown | 1 | 33% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 2 | 67% |
Science communicators (journalists, bloggers, editors) | 1 | 33% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 45 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 8 | 18% |
Student > Bachelor | 5 | 11% |
Researcher | 5 | 11% |
Student > Master | 4 | 9% |
Student > Doctoral Student | 2 | 4% |
Other | 6 | 13% |
Unknown | 15 | 33% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 16 | 36% |
Agricultural and Biological Sciences | 9 | 20% |
Medicine and Dentistry | 4 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 2% |
Neuroscience | 1 | 2% |
Other | 0 | 0% |
Unknown | 14 | 31% |