title: Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer.
abstract: Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Becker
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Annabell S
authors.initials: AS
authors.lastname: Oh
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Dedra H
authors.initials: DH
authors.lastname: Fagan
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Byron
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011379:Prognosis; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis
chemical_list: C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D009363:Neoplasm Proteins; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2