PHORBOL ESTERS INDUCE DEATH IN MCF-7 BREAST-CANCER CELLS WITH ALTERED EXPRESSION OF PROTEIN-KINASE-C ISOFORMS - ROLE FOR P53-INDEPENDENT INDUCTION OF GADD45 IN INITIATING DEATH

Protein kinase C (PKC) modulates growth, differentiation, and apoptosis in a cell-specific fashion, Overexpression of PKC-alpha in MCF-7 breast cancer cells (MCF-7-PKC-alpha cell) leads to expression of a more transformed phenotype, The response of MCF-7 and MCF-7-PKC-alpha cells to phorbol esters (TPA) was examined. TPA-treated MCF-7 cells demonstrated a modest cytostatic response associated with a G(1) arrest that was accompanied by Cip1 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-alpha 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-alpha cells that maned at higher concentrations, TPA-treated MCF-7-PKC-alpha cells accumulated in G(2)/M, did not express p53, displayed decreased Cip1 expression, and demonstrated a reduction in retinoblastoma hypophosphorylation, TPA-treated pressed gadd45 which 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 of gadd45 in a p53-independent fashion.