Human Molecular Genetics Advance Access originally published online on April 13, 2005
Human Molecular Genetics 2005 14(11):1457-1463; doi:10.1093/hmg/ddi155
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Phytoestrogen exposure elevates PTEN levels
1Clinical Cancer Genetics Program, Human Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA and 2Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 1XZ, UK
* To whom correspondence should be addressed at: Human Cancer Genetics Program, The Ohio State University, 420 W. 12th Avenue, Suite 690 TMRF, Columbus, OH 43210, USA. Tel: +1 6142922347; Fax: +1 6146883582; Email: eng-1{at}medctr.osu.edu
Received February 24, 2005; Accepted April 6, 2005
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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