Unknown

Dataset Information

0

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


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.

SUBMITTER: Ikink GJ 

PROVIDER: S-EPMC5122961 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3204389 | biostudies-literature
| S-EPMC8192787 | biostudies-literature
| S-EPMC8034842 | biostudies-literature
| S-EPMC3812138 | biostudies-literature
| S-EPMC5805360 | biostudies-literature
| S-EPMC3049391 | biostudies-literature
| S-EPMC5530910 | biostudies-literature
2012-09-06 | E-GEOD-33285 | biostudies-arrayexpress
| S-EPMC7773370 | biostudies-literature
| S-EPMC8300234 | biostudies-literature