The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and inducesapoptosis and anoikis in breast cancer cells

The PTEN/MMAC1/TEP (PTEN) tumor suppressor gene at 10q23.3 is mutated in mu ltiple types of sporadic tumors including breast cancers and also in the ge rmline of patients with the Cowden's breast cancer predisposition syndrome. The PTEN gene encodes a multifunctional phosphatase capable of dephosphory lating the same sites in membrane phosphatidylinositols phosphorylated by p hosphatidylinositol 3'-kinase (PI3K). We demonstrate herein that loss of PT EN function in breast cancer cells results in an increase in basal levels o f phosphorylation of multiple components of the P13K signaling cascade as w eb as an increase in duration of ligand-induced signaling through the P13K cascade. These alterations are reversed by wild-type but not phosphatase in active PTEN. In the presence of high concentrations of serum, enforced expr ession of PTEN induces a predominant G1 arrest consistent with the capacity of PTEN to evoke increases in the expression of the p27Kip1 cyclin depende nt kinase inhibitor. In the presence of low concentrations of serum, enforc ed PTEN expression results in a marked increase in cellular apoptosis, a fi nding which is consistent with the capacity of PTEN to alter the phosphoryl ation, and presumably function, of the AKT, BAD, p70S6 kinase and GSK3 alph a apoptosis regulators. Under anchorage-independent conditions, PTEN also i nduces anoikis, a form of apoptosis that occurs when cells are dissociated from the extracellular matrix, which is enhanced in conjunction with low se rum culture conditions. Together, these data suggest that PTEN effects on t he PI3K signaling cascade are influenced by the cell stimulatory context, a nd that depending on the exposure to growth factors and other exogenous sti muli such as integrin ligation, PTEN can induce cell cycle arrest, apoptosi s or anoikis in breast cancer cells.