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Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop
1Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada.
Abstract:
MCF-7 human breast cancer cells are commonly used to model tissues responsive to estrogens and antiestrogens. We examined the effects of estradiol and the antiestrogen ICI 182780 on MCF-7 cell proliferation and insulin-like growth factor binding protein 3 (IGFBP-3) gene expression. ICI 182780-induced growth inhibition was associated with increased transcription of the IG-FBP-3 gene, increased IGFBP-3 mRNA abundance, and increased IGFBP-3 protein accumulation in the conditioned medium. The growth stimulatory effect of estradiol was associated with opposite effects, and the correlation between cellular proliferation and IGFBP-3 mRNA abundance was strong (r = -0.91). Recombinant IGFBP-3 inhibited basal and estradiol-stimulated MCF-7 cell proliferation, and an IGFBP-3 antisense oligodeoxynucleotide abolished antiestrogen-induced growth inhibition. These results provide evidence for an estradiol and antiestrogen-regulated IGFBP-3 growth inhibitory autocrine pathway in MCF-7 cells.
Insights
Estradiol and antiestrogen treatments affect breast cancer cell growth. Antiestrogen ICI 182780 increases insulin-like growth factor binding protein 3 (IGFBP-3), inhibiting cell proliferation via an autocrine pathway.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- MCF-7 human breast cancer cells are a standard model for estrogen- and antiestrogen-responsive tissues.
- Estrogens and antiestrogens play critical roles in breast cancer development and treatment.
Purpose of the Study:
- To investigate the effects of estradiol and the antiestrogen ICI 182780 on MCF-7 cell proliferation.
- To elucidate the role of insulin-like growth factor binding protein 3 (IGFBP-3) in mediating these effects.
Main Methods:
- MCF-7 cells were treated with estradiol and/or ICI 182780.
- Gene expression, mRNA abundance, and protein accumulation of IGFBP-3 were analyzed.
- Cell proliferation assays were performed using recombinant IGFBP-3 and an IGFBP-3 antisense oligodeoxynucleotide.
Main Results:
- ICI 182780 treatment led to increased IGFBP-3 gene transcription, mRNA, and protein levels, correlating with growth inhibition.
- Estradiol exhibited opposite effects, stimulating proliferation and decreasing IGFBP-3 levels.
- Recombinant IGFBP-3 inhibited MCF-7 cell proliferation, while an antisense oligodeoxynucleotide blocked antiestrogen-induced growth inhibition.
Conclusions:
- Results indicate a strong inverse correlation between MCF-7 cell proliferation and IGFBP-3 mRNA abundance.
- An estradiol and antiestrogen-regulated IGFBP-3 growth inhibitory autocrine pathway exists in MCF-7 cells.