Phosphatidylinositol 3-kinase mediates heregulin-induced growth inhibition in human epithelial cells

Activation of phosphatidylinositol 3-kinase (PI-3K) has been shown to be critical for heregulin induced mitogenesis of human breast epithelial cells. However, the inhibitory effects of HRG have not been linked to PI3K activation The purpose of these experiments was to determine the effects of heregulin beta 1 (HRG) on growth and PI3K activation of a nonneoplastic human mammary epithelial cell line, 184B5. The results of these experiments indicated that low concentrations of HRG increased the growth of 184B5 cells three fold, while high concentrations inhibited growth by 50%. HRG at all concentrations tested increased tyrosine phosphorylation of erbB3. Similarly, HRG at all concentrations stimulated the association of PI3K with erbB3. Wortmannin, an inhibitor of PI3K enzymatic activity, reversed both the inhibitory and stimulatory effects of HRG on incorporation of [H-3] thymidine into DNA. We conclude that both the growth inhibitory and stimulatory effects of HRG in nonneoplastic human mammary epithelial cells are mediated by activation of PI3K.