Role of IRS-1 Signaling in Insulin-Induced Modulation of Estrogen Receptors in Breast Cancer Cells

doi:10.1006/bbrc.1998.9330

Biochemical and Biophysical Research Communications

Volume 253, Issue 2, 18 December 1998, Pages 315-319

https://doi.org/10.1006/bbrc.1998.9330 Get rights and content

Abstract

Cross-talk between steroid hormones and polypeptide growth factors regulates the growth of hormone-responsive breast cancer cells. For example, in the MCF-7 human breast cancer cell line, insulin up-regulates estrogen receptor (ER) content and binding capacity. Since the insulin receptor (IR) substrate 1 (IRS-1) is one of the core signaling elements transmitting mitogenic and metabolic effects of insulin, we investigated whether IRS-1 is also required for the insulin-induced function of the ER. The effects of insulin on the ER were compared in MCF-7 cells and MCF-7-derived cell lines with decreased levels (by ∼80%) of IRS-1 due to the expression of IRS-1 antisense RNA. The severe IRS-1 deficiency in MCF-7 cells was associated with (1) reduced mitogenic response to 20 ng/ml insulin and 10% calf serum (CS), but not to 1 nM estradiol (E2); (2) loss of insulin-E2 synergism; (3) up-regulation of ER protein expression and binding capacity; and (4) loss of insulin-induced regulation of ER tyrosine phosphorylation. In conclusion, the data confirm the existence of the IR–ER cross-talk and suggest that IRS-1-dependent signaling may contribute to the negative regulation of the ER expression and function in MCF-7 cells.

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Citation Excerpt :
Estrogen has been implicated in the suppression of hepatic glucose production and the protection of β-cell function and insulin secretion under conditions of oxidative stress [29]. In addition, ER-α can co-modulate with insulin receptor substrate 1 (IRS1) to affect insulin signaling and action [30]. A previous report confirmed the association between the C allele of the PvuII polymorphism and the absence of expression of the ESR1 gene [31].
Metabolic syndrome is a risk factor for coronary heart diseases as well as diabetes, fatty liver and several cancers. The prevalence of metabolic syndrome in women appears to be increasing, particularly in women of childbearing age. In the present study, we assessed the association of estrogen receptor-alpha gene polymorphisms (XbaI and PvuII) with metabolic syndrome and its related phenotypes.
One hundred and fifty Egyptian female patients with metabolic syndrome (mean age 35.52 ± 6.86) were compared with one hundred and fifty age matched healthy Egyptian women (controls). The component traits of metabolic syndrome were determined, and the XbaI and PvuII genotypes were assessed with the PCR-RFLP method.
Our data indicated a significant difference in the allele frequencies of XbaI, but not PvuII, between the metabolic syndrome and control groups (P = 0.0003 and P = 0.164). Carriers of the minor alleles of XbaI and PvuII gene polymorphisms, in either the homozygous or heterozygous form, were associated with high diastolic blood pressure, high total cholesterol and LDL-c levels, increased HOMA-IR values and decreased QUICKI values compared to carriers of the major allele. However, only the minor G allele of XbaI was associated with measures of adiposity, specifically, BMI and waist circumference.
The XbaI polymorphism of the estrogen receptor alpha gene is associated with metabolic syndrome. On the other hand, PvuII gene polymorphism is not associated with the occurrence of the disease in this sample of Egyptian women.
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Insulin regulates metabolism through homologous receptor tyrosine kinases, and plays a role in proliferation of breast cancer cells. Our research studied whether insulin, administered separately or in combination with paclitaxel, interferes with paclitaxel-mediated biological activity in human breast cancer cells. Not only did insulin influence paclitaxel-mediated cell microtubule reorganization, but it also influenced MCF-7 cell sensitivity to paclitaxel. Furthermore, combined administrations of insulin and paclitaxel affected MAPK pathway, Raf-1 activation and p53 expression levels. Our findings indicate that insulin seems to modulate MCF-7 cell response to paclitaxel; consequently, elevated levels of insulin could influence tumor cell resistance.
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Several findings indicate that there is a close interaction between estrogen and insulin-like growth factor I in different brain regions. In adult brain, both estrogen and insulin-like growth factor I have co-ordinated effects in the regulation of neuroendocrine events, synaptic plasticity and neural response to injury. In this study we have qualitatively assessed whether estrogen receptors and insulin-like growth factor I receptor are colocalized in the same cells in the preoptic area, hypothalamus, hippocampus, cerebral cortex and cerebellum of female rat brain using confocal microscopy. Immunoreactivity for estrogen receptors α and β was colocalized with immunoreactivity for insulin-like growth factor I receptor in many neurons from the preoptic area, hypothalamus, hippocampus and cerebral cortex. Furthermore, estrogen receptor β and insulin-like growth factor I receptor immunoreactivities were colocalized in the Purkinje cells of the cerebellum. Colocalization of estrogen receptor β and insulin-like growth factor I receptor was also detected in cells with the morphology of astrocytes in all regions assessed. The co-expression of estrogen receptors and insulin-like growth factor I receptor in the same neurons may allow a cross-coupling of their signaling pathways. Furthermore, the colocalization of immunoreactivity for estrogen receptor β and insulin-like growth factor I receptor in glial cells suggests that glia may also play a role in the interactions of insulin-like growth factor I and estrogen in the rat brain.
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^☆: Harris, J. R.Lippmann, M. E.Morrow, M.Hellman, S.

¹: To whom correspondence should be addressed at Dipartimento di Biologia Cellulare, Universita' degli Studi della Calabria, 87036 Rende, Cosenza, Italy. Fax: 011-39-984-493160. E-mail:[email protected].

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Regular ArticleRole of IRS-1 Signaling in Insulin-Induced Modulation of Estrogen Receptors in Breast Cancer Cells☆

Abstract

Biomed. Pharmacother.

FEBS Lett.

Diseases of the Breast

Endocrine Rev.

Breast Cancer Res. Treatm.

EMBO J.

Ann. N.Y. Acad. Sci.

Cancer Res.

Biol. Reprod.

J. Cancer Res. Clin.

Science

Mol. Endocrinol.

Mol. Endocrinol.

Regular Article
Role of IRS-1 Signaling in Insulin-Induced Modulation of Estrogen Receptors in Breast Cancer Cells☆