Epidemiological data suggest that consumption of
phytoestrogens can be protective against the development of
breast cancer. It may be logical to postulate that
phytoestrogens may regulate
proteins that control cellular division, such as the
tumor suppressor PTEN. Germline, and more significantly, somatic PTEN mutations have been observed in a broad range of human
cancers, especially those of the breast. Active PTEN results in decreased phosphorylation of Akt and MAPK, the up-regulation of p27 and down-regulation of
cyclin D1 protein levels resulting in decreased proliferation and an increase in apoptosis. We hypothesized that
phytoestrogen exposure regulates
PTEN protein expression in the
breast cancer cell line, MCF-7. When MCF-7 cells were stimulated with
resveratrol,
quercetin or
genistein, there was an increase in
PTEN protein levels. Concomitantly,
phytoestrogen stimulation resulted in decreased Akt phosphorylation and an increase in p27
protein levels, indicating active PTEN
lipid phosphatase activity. In contrast, we found that MAPK phosphorylation and
cyclin D1 levels, which are regulated by PTEN's
protein phosphatase activity, were not altered. Using semi-quantitative RT-PCR, we found that
mRNA levels were slightly increased in cells stimulated by
phytoestrogens, suggesting that the mechanism for increased
PTEN protein expression is dependent upon transcription. Concurrently, our data provide evidence that a mechanism for
phytoestrogens' protective nature is partially through increased PTEN expression. More importantly, it provides a novel target for the regulation of PTEN expression and suggests that dietary changes may be adjunctive to traditional preventive and therapeutic strategies against
breast cancer.