Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

Abstract

Activation of the type I insulin-like growth factor receptor (IGF-IR) regulates several aspects of the malignant phenotype, including cancer cell proliferation and metastasis. Phosphorylation of adaptor proteins downstream of IGF-IR may couple IGF action to specific cancer phenotypes. In this study, we sought to determine if insulin receptor substrate-1 and -2 (IRS-1 and -2) mediate distinct biological effects in breast cancer cells. Insulin receptor substrate-1 and IRS-2 were expressed in T47D-YA breast cancer cells, which lack IRS-1 and -2 expression, yet retain functional IGF-IR. In the absence of IRS-1 and -2 expression, IGF-IR activation was unable to stimulate proliferation or motility in T47D-YA cells. Expression of IRS-1 resulted in IGF-I-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-I-stimulated motility, but did not stimulate proliferation. The aIR-3, an inhibitor of the IGF-IR, was unable to affect these IGF-stimulated phenotypes unless IRS-1 or -2 was expressed. Thus, IGF-IR alone is unable to regulate important breast cancer cell phenotypes. In these cells, IRS proteins are required for and mediate distinct aspects of IGF-IRstimulated behaviour. As multiple agents targeting the IGF-IR are currently in early clinical trials, IRS expression should be considered as a potential biomarker for IGF-IR responsiveness.

Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells

“…1C and S1) (5). IRS-1 is a key mediator of IGF-1-dependent breast cancer cell proliferation (17). We reasoned that cells expressing K388R PR-B should be more responsive to IGF-1 due to PR-dependent elevated IRS-1 expression.…”

“…The transcription of IRS-1 is PR-B driven and requires Ser-294 phosphorylation, but also occurs in the absence of progestins (3). IRS-1 is an adaptor molecule in the IGF receptor pathway that is critical for IGF-1 mediated proliferation of breast cancer cells (17). We therefore tested whether IRS-1 expression was sensitive to PR sumoylation using real-time PCR in T47D cells stably expressing either wt, S294A or K388R PR-B.…”

Predictive biomarkers for targeting insulin-like growth factor-I (IGF-I) receptor

“…The identification of such biomarkers remains arguably the most important issue in development of drugs targeting IGF-IR. Previous studies have reported on the expression of IGF1-R, phospho-IGF-IR, insulin receptor substrates-1 (IRS1), and -2 (IRS2), and predictive gene expression signatures (10)(11)(12)(13). This report describes a detailed assessment of certain elements of the pathway, including an evaluation of the receptor and its ligands, and its proximal and distal signaling proteins with expression array profiles, focusing exclusively on breast and colorectal cancer (CRC) models.…”

Depletion of insulin receptor substrate 2 reverses oncogenic transformation induced by v-src

“…There have been reports that delta-PHPTB IRS-2 may have biological activity [16,17] . The delta-PHPTB IRS-2 is fully capable (as is wild type IRS-2 and IRS-1) of both stimulating growth and inhibiting differentiation of 32D-IGF-1R cells.…”

“…In contrast, IRS-1 proteins lacking the same PH and PTB domains are completely inactive in blocking differentiation and stimulating IL-3-independent growth of 32D-IGF-1R cells [6] . Down-regulation of IRS-2 may affect the protein's nuclear functions, bypassing its conventional signaling pathway [17,18] .…”