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Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line

Lookup NU author(s): Dr Felicity May, Professor Bruce Westley


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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.

Publication metadata

Author(s): Molloy CA, May FEB, Westley BR

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2000

Volume: 275

Issue: 17

Pages: 12565-12571

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X


DOI: 10.1074/jbc.275.17.12565


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