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Insulin receptor substrate adaptor proteins mediate prognostic gene expression profiles in breast cancer

Becker, MA and Ibrahim, YH and Oh, AS and Fagan, DH and Byron, SA and Sarver, AL and Lee, AV and Shaw, LM and Fan, C and Perou, CM and Yee, D (2016) Insulin receptor substrate adaptor proteins mediate prognostic gene expression profiles in breast cancer. PLoS ONE, 11 (3).

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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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Becker, MA
Ibrahim, YH
Oh, AS
Fagan, DH
Byron, SA
Sarver, AL
Lee, AVavl10@pitt.eduAVL10
Shaw, LM
Fan, C
Perou, CM
Yee, D
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 1 March 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 11
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0150564
Institution: University of Pittsburgh
Refereed: Yes
Date Deposited: 23 Aug 2016 15:11
Last Modified: 30 Mar 2021 17:55
URI: http://d-scholarship.pitt.edu/id/eprint/28292

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