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

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 17β-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 (10⁻⁶m) caused stimulation of precursor IGF-II mRNA and protein; this effect was blocked by coincubation with 17β-estradiol (10⁻⁹m). Cell growth stimulated by RSV (10⁻⁶m) was blocked by addition of a blocking IGF-I receptor antibody, or the antiestrogen tamoxifen (10⁻⁷m). In contrast, RSV treatment (10⁻⁴m) 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 10⁻⁴m and precursor IGF-II blocked the inhibitory effect of resveratrol. No change in IGF-I was observed with RSV treatment (10⁻⁶ to 10⁻⁴m). Our study demonstrates that RSV regulates IGF-II and that IGF-II mediates RSV effect on cell survival and growth in breast cancer cells.