Role of insulin-like growth factor-I in regulating estrogen receptor-α gene expression

Adriana Stoica, Miguel Saceda, Amina Fakhro, Michael Joyner, Mary Beth Martin

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    Abstract

    The role of insulin-like growth factor-I (IGF-I) in regulating estrogen receptor-α (ER-α) gene expression and activity was investigated in the human breast cancer cell line MCF-7. Treatment of cells with 40 ng/ml IGF-I resulted in a 60% decrease in ER-α protein concentration by 3 h, and the amount of ER-α remained suppressed for 24 h. A multiple-dose ligand-binding assay demonstrated that the decrease in ER-α protein corresponded to a similar decrease of 50% in estradiol-binding sites with no effect on the binding affinity of ER-α. The dissociation constant of the estradiol-ER-α complex in the absence of IGF-I (K(d)= 3 x 10-10 ± 0.5 x 10-10 M) was similar to the dissociation constant in the presence of IGF-I (K(d)= 6 X 10-10 + 0.3 X 10-10 M). The decrease in ER-α protein concentration was paralleled by an 80% decrease in the steady-state amount of ER-α mRNA by 3 h. The IGF-I induced decrease in ER-α mRNA was due to the inhibition of ER- α gene transcription. When an 128-base pair ER-α-promoter-CAT construct was transfected into MCF-7 cells, treatment with IGF-I resulted in a 40% decrease in CAT activity, n contrast to the effects on ER-α, treatment with IGF-I induced two endogenous estrogen-regulated genes, progesterone receptor and pS2, by 4- and twofold, respectively. The pure antiestrogen IO-164,384 blocked this induction, suggesting that ER-α mediates the effects of IGF-I. Transient co-transfections of wild-type ER-α and an estrogen response element-CAT reporter into COS-1 cells demonstrated that IGF-I increased reporter gene activity. This effect was also blocked by ICI 164,384. Protein kinase A and phosphatidylinositol 3-kinase inhibitors blocked the IGF-I effects on ER-eα expression and activity, suggesting that these kinases may be involved in the cross-talk between the IGF-I and ER-α pathways. (C) 2000 Wiley-Liss, Inc.

    Original languageEnglish
    Pages (from-to)605-614
    Number of pages10
    JournalJournal of Cellular Biochemistry
    Volume76
    Issue number4
    DOIs
    Publication statusPublished - 1 Jan 2000

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    Keywords

    • ER-α IGF-I effects
    • Gene expression

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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