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PTEN Suppresses Breast Cancer Cell Growth by Phosphatase Activity-dependent G₁ Arrest followed by Cell Death¹

Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210 [L-P. W., W. M. S., P. L. M. D., C. E.]; Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [P. L. M. D.]; Department of Biology, Cancer Research Center, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [U. Z., E. G., J. A. L.]; and CRC Human Cancer Genetics Research Group, University of Cambridge, Cambridge UK CB2 2QQ, United Kingdom [C. E.]

PTEN/MMAC1/TEP1, a tumor suppressor gene, is frequently mutated in a variety of human cancers. Germ-line mutations of phosphatase and tensin homolog, deleted on chromosome ten (PTEN) are found in two inherited hamartoma tumor syndromes: Cowden syndrome, which has a high risk of breast, thyroid, and other cancers; and Bannayan-Zonana syndrome, a related disorder. PTEN encodes a phosphatase that recognizes both protein substrates and phosphatidylinositol-3,4,5-triphosphate. The lipid phosphatase activity of PTEN seems to be important for growth suppression through inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. We established clones with stable PTEN expression controlled by a tetracycline-inducible system to examine the consequences of increased levels of wild-type and mutant PTEN expression in a well-characterized breast cancer line, MCF-7. When we overexpressed PTEN in MCF-7, growth suppression was observed, but only if PTEN phosphatase activity is preserved. The initial growth suppression was attributable to G₁ cell cycle arrest, whereas subsequent growth suppression was attributable to a combination of G₁ arrest and cell death. Of note, the decrease in Akt phosphorylation preceded the onset of suppression of cell growth. Treatment of MCF-7 cells with wortmannin, a PI3K inhibitor, caused cell growth inhibition in a way similar to the effects of overexpression of PTEN in this cell. In general, the inverse correlation between PTEN protein level and Akt phosphorylation was found in a panel of breast cancer cell lines. Therefore, PTEN appears to suppress breast cancer growth through down-regulating PI3K signaling, which leads to the blockage of cell cycle progression and the induction of cell death, in a sequential manner.

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