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J Biol Chem, Vol. 275, Issue 17, 12565-12571, April 28, 2000
From the Department of Pathology, Royal Victoria Infirmary,
Newcastle-upon-Tyne NE1 4LP, United Kingdom
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.
Insulin Receptor Substrate-1 Expression Is Regulated by Estrogen
in the MCF-7 Human Breast Cancer Cell Line*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by funds from the University of Newcastle-upon-Tyne and
the North of England Cancer Research Campaign.
§
To whom correspondence should be addressed. Tel.: 191-222-6000, Ext. 7200; Fax: 191-222-8100; E-mail: b.r.westley@ncl.ac.uk.
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