Growth inhibition of MCF-7 human breast cancer cells by progesterone is associated with cell differentiation and phosphorylation of Akt protein.

Progesterone inhibits the proliferation of normal breast epithelial cells as well as breast cancer cells. The molecular mechanisms of this inhibition are not fully understood. The purpose of this study was to investigate the capacity of progesterone to induce apoptosis and to alter the activity of a key regulator of cell growth and differentiation, the Akt protein. We show here that (i) growth inhibition of breast cancer cells by progesterone is due to the induction of cell differentiation and not to apoptosis; (ii) progesterone activates the PI3-kinase/Akt pathway as shown by the increase in the phosphorylation of Akt protein; (iii) inhibiting PI3-kinase/Akt pathway with LY294002 causes stimulation of apoptosis; and (v) progesterone enhances LY294002 induced-growth inhibition and apoptosis. These results suggest that progesterone may protect breast cancer cells from apoptosis by altering PI3-kinase activity and that MCF-7 cells become more sensitive to progesterone and die by apoptosis upon inhibition of the PI3-kinase/Akt pathway.