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

S. A. Byron, K. B. Horwitz, J. K. Richer, Carol A Lange, Xihong Zhang, Douglas Yee

Research output: Contribution to journalArticle

91 Citations (Scopus)

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 αIR-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-IR-stimulated 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.

Original languageEnglish (US)
Pages (from-to)1220-1228
Number of pages9
JournalBritish Journal of Cancer
Volume95
Issue number9
DOIs
StatePublished - Nov 6 2006

Fingerprint

Somatomedin Receptors
Insulin Receptor
Insulin Receptor Substrate Proteins
Breast Neoplasms
Phenotype
Insulin-Like Growth Factor I
IGF Type 1 Receptor
Insulin-Like Growth Factor II
Neoplasms
Proteins
Biomarkers
Phosphorylation
Cell Proliferation
Clinical Trials
Neoplasm Metastasis

Keywords

  • Insulin receptor substrate
  • Insulin-like growth factor-I
  • Motility
  • Proliferation
  • Type I insulin-like growth factor receptor

Cite this

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells. / Byron, S. A.; Horwitz, K. B.; Richer, J. K.; Lange, Carol A; Zhang, Xihong; Yee, Douglas.

In: British Journal of Cancer, Vol. 95, No. 9, 06.11.2006, p. 1220-1228.

Research output: Contribution to journalArticle

@article{14d71202541140bf85bc199fc11f9b2a,
title = "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 αIR-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-IR-stimulated 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.",
keywords = "Insulin receptor substrate, Insulin-like growth factor-I, Motility, Proliferation, Type I insulin-like growth factor receptor",
author = "Byron, {S. A.} and Horwitz, {K. B.} and Richer, {J. K.} and Lange, {Carol A} and Xihong Zhang and Douglas Yee",
year = "2006",
month = "11",
day = "6",
doi = "10.1038/sj.bjc.6603354",
language = "English (US)",
volume = "95",
pages = "1220--1228",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

AU - Byron, S. A.

AU - Horwitz, K. B.

AU - Richer, J. K.

AU - Lange, Carol A

AU - Zhang, Xihong

AU - Yee, Douglas

PY - 2006/11/6

Y1 - 2006/11/6

N2 - 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 αIR-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-IR-stimulated 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.

AB - 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 αIR-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-IR-stimulated 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.

KW - Insulin receptor substrate

KW - Insulin-like growth factor-I

KW - Motility

KW - Proliferation

KW - Type I insulin-like growth factor receptor

UR - http://www.scopus.com/inward/record.url?scp=33750453743&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750453743&partnerID=8YFLogxK

U2 - 10.1038/sj.bjc.6603354

DO - 10.1038/sj.bjc.6603354

M3 - Article

C2 - 17043687

AN - SCOPUS:33750453743

VL - 95

SP - 1220

EP - 1228

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 9

ER -