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J. Biol. Chem., Vol. 276, Issue 43, 40080-40086, October 26, 2001
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From the Division of Cell and Molecular Biology, School of Animal
and Microbial Sciences, the University of Reading, Whiteknights,
P. O. Box 228, Reading RG6 6AJ, United Kingdom
This work describes a reciprocal relationship
between cell density and levels of insulin-like growth factor receptors
(IGFR) in MCF7 human breast cancer cells, which adds a new dimension to
the mechanism of cross-talk between estrogen and insulin-like growth
factors in the regulation of breast cancer cell growth. The reduced
binding of both 125I-IGF1 and
Insulin-like Growth Factor Receptor Levels Are
Regulated by Cell Density and by Long Term Estrogen Deprivation
in MCF7 Human Breast Cancer Cells*
IR3 anti-IGFR
antibody to whole cells showed that IGFR are lost from the surface of
MCF7 cells as cell density increases, and this occurred irrespective of
the presence or absence of estradiol. Western immunoblotting further
confirmed loss of type I IGFR from MCF7 cells with increasing cell
density. Long term estrogen deprivation was found to increase the
levels of IGFR at all cell densities, such that after 96 weeks of
estrogen deprivation, IGFR levels had become similar at the highest
cell density in the absence of estradiol to the IGFR levels at the
lowest cell density in the estrogen-maintained cells, and the levels of
IGFR could be increased still further by estradiol. This overexpression
of IGFR in the estrogen-deprived cells correlated with a reversal of
response to exogenously added ligand, in that concentrations of
insulin, IGFI, and IGFII that had stimulated growth of the
estrogen-maintained cells became growth inhibitory to the
estrogen-deprived cells. Blockade of the IGFIR with the IR3
anti-IGFR antibody could partially inhibit the growth of the
estrogen-deprived cells, suggesting that up-regulation of IGFR in these
cells may contribute to the mechanism of adaptation to growth in
steroid-deprived conditions which results in progression to estrogen
independence of cell growth.
*
This work was supported by the Felix Foundation (to R. S.),
the Association for International Cancer Research (to D. C.), and the
Breast Cancer Campaign (to L. E. S. and P. D. D.).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.
To whom correspondence should be addressed. Tel.:
44-118-9875123 (Ext. 7035/7025); Fax: 44-118-9310180; E-mail:
p.d.darbre@reading.ac.uk.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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