PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G(1) arrest followed by cell death

PTEN/MMAC1/TEP1, a tumor suppressor gene, is frequently mutated in a variet y 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 encod es a phosphatase that recognizes both protein substrates and phosphatidylin ositol-3,4,5-triphosphate. The Lipid phosphatase activity of PTEN seems to be important for growth suppression through inhibition of the phosphatidyli nositol 3-kinase (PI3K)/Akt signaling pathway. We established clones with s table PTEN expression controlled by a tetracycline-inducible system to exam ine the consequences of increased levels of mild-type and mutant PTEN expre ssion in a well-characterized breast cancer line, MCF-7. When we overexpres sed PTEN in MCF-7, growth suppression was observed, but only if PTEN phosph atase activity is preserved. The initial growth suppression was attributabl e to G(1) cell cycle arrest, whereas subsequent growth suppression was attr ibutable to a combination of G(1) arrest and cell death. Of note, the decre ase in Akt phosphorylation preceded the onset of suppression of cell growth . Treatment of MCF-7 cells with wortmannin, a PI3K inhibitor, caused cell g rowth inhibition in a way similar to the effects of overexpression of PTEN in this cell. In general, the inverse correlation between PTEN protein leve l and Akt phosphorylation was found in a panel of breast cancer cell lines. Therefore, PTEN appears to suppress breast cancer growth through down-regu lating PI3K signaling, which Leads to the blockage of cell cycle progressio n and the induction of cell death, in a sequential manner.