Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line.
Estrogens can stimulate the proliferation of estrogen-responsive breast cancer cells by increasing their proliferative response to insulin-like growth factors. The mechanism underlying the increased proliferation could involve the induction of components of the insulin-like growth factor signal transduction pathway by estrogen. In this study we have examined the regulation of the expression of insulin receptor substrate-1, a major intracellular substrate of the type I insulin-like growth factor receptor tyrosine kinase. Estradiol increased insulin receptor substrate-1 mRNA and protein levels at concentrations consistent with a mechanism involving the estrogen receptor. Insulin receptor substrate-1 was not induced significantly by the antiestrogens tamoxifen and ICI 182,780, but they inhibited the induction of insulin receptor substrate-1 by estradiol. Analysis of tyrosine-phosphorylated insulin receptor substrate-1 showed that the highest levels were found in cells stimulated by estradiol and insulin-like growth factor-I, whereas low levels were found in the absence of estradiol irrespective of whether type I insulin-like growth factor ligands were present. Insulin receptor substrate-2, -3, and -4 were not induced by estradiol. These results suggest that estrogens and antiestrogens may regulate cell proliferation by controlling insulin receptor substrate-1 expression, thereby amplifying or attenuating signaling through the insulin-like growth factor signal transduction pathway.
Molloy
C A
CA
Department of Pathology, Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP, United Kingdom.
May
F E
FE
Westley
B R
BR
D048868:Adaptor Proteins, Signal Transducing; D015152:Blotting, Northern; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012313:RNA / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D004967:Estrogens; C526292:IRS1 protein, human; C526297:IRS2 protein, human; C491585:IRS3P protein, human; C107686:IRS4 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C491531:Irs4 protein, mouse; D010750:Phosphoproteins; D013629:Tamoxifen; D014443:Tyrosine; D004958:Estradiol; D012313:RNA; D017526:Receptor, IGF Type 1