Protein kinase C (PKC) modulates growth, differentiation, and apoptosis in a cell-specific fashion. Overexpression of PKC-a in MCF-7 breast cancer cells (MCF-7-PKC-a cell) leads to expression of a more transformed phenotype. The response of MCF-7 and MCF-7-PKC-c cells to phorbol esters (TPA) was examined. TPA-treated MCF-7 cells demonstrated a modest cytostatic response associated with a G, arrest that was accompanied by Cipl expression and retinoblastoma hypophosphorylation. While p53 was detected in MCF-7 cells, evidence for TPA-induced stimulation of p53 transcriptional activity was not evident. In contrast, TPA treatment induced death of MCF-7-PKC-a cells. Bryostatin 1, another PKC activator, exerted modest cytostatic effects on MCF-7 cells while producing a cytotoxic response at low doses in MCF-7-PKC-a cells that waned at higher concentrations. TPA-treated MCF-7-PKC-a cells accumulated in G2/M, did not express p53, displayed decreased Cipl expression, and demonstrated a reduction in retinoblastoma hypophosphorylation. TPA-treated MCF-7-PKC-a cells expressed gadd45 which occurred before the onset of apoptosis. Thus, alterations in the PKC pathway can modulate the decision of a breast cancer cell to undergo death or differentiation. In addition, these data show that PKC activation can induce expression ofgadd45 in a p53-independent fashion. (J.