NDF/heregulin-induced cell cycle changes and apoptosis in breast tumour cells: role of PI3 kinase and p38 MAP kinase pathways

Neu differentiation factor (NDF)/heregulin activates ErbB2 via heterodimeri zation with the NDF receptors ErbB3 and ErbB4. Cells which express normal l evels of these receptors are often growth stimulated by NDF, whereas SKBR3, and other ErbB2-overexpressing breast tumour cells are growth inhibited. W e demonstrate here that in SKBR3 cells, NDF induces G1 progression but also causes a G2 delay from day 1 and apoptosis from days 2-3. G1 progression w as associated with ErbB2 transactivation of ErbB3 and subsequent stimulatio n of the phosphatidylinositol 3-kinase (PI3K) whereas apoptosis was depende nt on p38 MAPK. Inhibition of ERK1/ERK2 had no effect on cell cycle progres sion or apoptosis. Activation of ErbB3 and PI3K was also seen with betacell ulin (BTC) but not epidermal growth factor (EGF) and. correlated with the g rowth effects of these ligands. All three ligands induced shortterm activat ion of p38 MAPK in a c-Src-dependent manner. However, only NDF caused a sec ond, c-Src-independent increase in p38 MAPK activity which was required for apoptosis.