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, 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. Since E₂ 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 (proIGF-II) mRNA and protein; this effect was blocked by coincubation with E₂ (10^-9 M). Cell growth stimulated by RSV (10^-6M) was blocked by addition of a blocking IGF-I receptor (IGF-IR) antibody, or the antiestrogen tamoxifen (10^-7 M). 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 ER (-) MCF-10 cells, even though cell growth was inhibited by RSV 10^-4 M and proIGF-II blocked the inhibitory effect of resveratrol. No change in IGF-I was observed with RSV treatment (10^-6M-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.