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Resveratrol Regulates Insulin-Like Growth Factor-II in Breast Cancer Cells

Departments of Anatomy (S.V.) and Physiology (Y.A., D.D.D.L.), Loma Linda University, Loma Linda, California 92350

Address all correspondence and requests for reprints to: Daisy D. De León, Ph.D., CSP 11012, Loma Linda University School of Medicine, Loma Linda, California 92350. E-mail: ddeleon{at}som.llu.edu.

IGF-II is a potent mitogen and inhibitor of apoptosis in breast cancer. Regulation of IGF-II is complex and includes inhibition by tumor suppressors, stimulation by oncogenes, and imprinting and hormonal regulation by estrogens. Resveratrol (RSV) is a phytoestrogen that displays estrogen-like agonistic and antagonistic activity. Recent studies have shown that RSV inhibits the growth of breast cancer cells and may represent a potent agent in chemopreventive therapy. Because 17ß-estradiol regulates IGF-II, we hypothesized that RSV may have a similar effect on IGF-II. The present study was designed to examine whether: 1) RSV modulates IGF-II in breast cancer cells; 2) regulation of IGF-II by RSV is dependent on the ER status; and 3) IGF-II (not IGF-I) mediates RSV effects on breast cancer cells. Treatment of MCF-7 and T47D cells with RSV (10^–6 M) caused stimulation of precursor IGF-II mRNA and protein; this effect was blocked by coincubation with 17ß-estradiol (10^–9 M). Cell growth stimulated by RSV (10^–6 M) was blocked by addition of a blocking IGF-I receptor antibody, or the antiestrogen tamoxifen (10^–7 M). In contrast, RSV treatment (10^–4 M) inhibited IGF-II secretion and cell growth in MCF-7 and T47D cells. No increase in IGF-II levels is seen in estrogen receptor (–) MCF-10 cells, even though cell growth was inhibited by RSV 10^–4 M and precursor IGF-II blocked the inhibitory effect of resveratrol. No change in IGF-I was observed with RSV treatment (10^–6 to 10^–4 M). Our study demonstrates that RSV regulates IGF-II and that IGF-II mediates RSV effect on cell survival and growth in breast cancer cells.

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