The p38 MAPK pathway is required for cell growth inhibition of human breast cancer cells in response to activin

Activin, a member of the TGF beta family inhibits cell growth in various ta rget tissues. Activin interacts with a complex of two receptors that upon a ctivation phosphorylate specific intracellular mediators, the Smad proteins . The activated Smads interact with diverse DNA binding proteins and co-act ivators of transcription in a cell-specific manner, thus leading to various activin biological effects. In this study, we investigated the role and me chanism of action of activin in the human breast cancer T47D cells. We foun d that activin treatment of T47D cells leads to a dramatic decrease in cell growth. Thus activin appears as a potent cell growth inhibitor of these br east cancer cells. We show that activin induces the Smad pathway in these c ells but also activates the p38-mitogen-activated protein kinase pathway, f urther leading to phosphorylation of the transcription factor ATF2. Finally , specific inhibitors of the p38 kinase (SB202190, SB203580, and PD169316) but not an inactive analogue (SB202474) or the MEK-1 inhibitor PD98059 comp letely abolish the activin-mediated cell growth inhibition of T47D cells. T ogether, these results define a new role for activin in human breast cancer T47D cells and highlight a new pathway utilized by this growth factor in t he mediation of its biological effects in cell growth arrest.