title: Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2.
abstract: Insulin receptor substrates (IRSs) are signaling adaptors that play a major role in the metabolic and mitogenic actions of insulin and insulin-like growth factors. Reports have recently noted increased levels, or activity, of IRSs in many human cancers, and some have linked this to poor patient prognosis. We found that overexpressed IRS-1 was constitutively phosphorylated in vitro and in vivo and that transgenic mice overexpressing IRS-1 or IRS-2 in the mammary gland showed progressive mammary hyperplasia, tumorigenesis, and metastasis. Tumors showed extensive squamous differentiation, a phenotype commonly seen with activation of the canonical beta-catenin signaling pathway. Consistent with this, IRSs were found to bind beta-catenin in vitro and in vivo. IRS-induced tumorigenesis is unique, given that the IRSs are signaling adaptors with no intrinsic kinase activity, and this supports a growing literature indicating a role for IRSs in cancer. This study defines IRSs as oncogene proteins in vivo and provides new models to develop inhibitors against IRSs for anticancer therapy.
authors.affiliation: Breast Cancer, Baylor College of Medicine and Methodist Hospital, Department of Medicine, Houston, TX 77030, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Dearth
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Lawrence
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.forename: Jana
authors.initials: J
authors.lastname: Divisova
authors.forename: Ora L
authors.initials: OL
authors.lastname: Britton
authors.forename: Syed
authors.initials: S
authors.lastname: Mohsin
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Darryl L
authors.initials: DL
authors.lastname: Hadsell
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002461:Cell Line, Transformed; D005260:Female; D006801:Humans; D006965:Hyperplasia; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D008321:Mammary Glands, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins