A role for protein kinase C delta in the differential sensitivity of MCF-7 and MDA-MB 231 human breast cancer cells to phorbol ester-induced growth arrest and p21(WAFI/CIP1) induction.

Abstract	The goal of this study was to investigate the differential sensitivity of estrogen receptor (ER) positive MCF-7 and ER negative MDA-MB 231 breast cancer cells to phorbol myristate acetate (PMA)-dependent growth arrest. MCF-7 cells were growth arrested by 80% while MDA-MB 231 cells were arrested by 20% in response to seven days of treatment with 10 nM PMA. Coincident with the increased sensitivity of MCF-7 cells to be growth arrested by the protein kinase C (PKC) activator PMA, PMA induced 9-fold higher levels of the cyclin dependent kinase (Cdk) inhibitor p21(WAF1/GIP1) in MCF-7 compared to MDA-MB 231 cells. A comparison of the PKC isoforms expressed in MCF-7 versus MDA-MB 231 cells showed that only the PMA-sensitive PKC delta and eta isoforms were expressed at markedly (> or =10-fold) elevated levels in MCF7 versus MDA-MB 231 cells. These results suggested that the differential sensitivity to growth arrest and induction of p2l(WAFl/CIPl) could reflect, at least in part, increased expression of PMA-dependent PKC isoforms delta and/or eta. Direct evidence to support this hypothesis was provided by the ability of transient transfections into MCF-7 cells of constitutively active PKC delta but not of PKC's eta or alpha or epsilon to enhance p21(WAFl/CIP1) promoter activity. These results suggest that PKC delta plays a fundamental role in the regulation of growth in estrogen receptor positive breast cancer cells.
Authors	M Shanmugam, N L Krett, E T Maizels, F M Murad, S T Rosen, M Hunzicker-Dunn
Journal	Cancer letters (Cancer Lett) Vol. 172 Issue 1 Pg. 43-53 (Oct 22 2001) ISSN: 0304-3835 [Print] Ireland
PMID	11595128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References	Acetophenones Benzopyrans CDKN1A protein, human Carcinogens Cdkn1a protein, rat Cyclin-Dependent Kinase Inhibitor p21 Cyclins Detergents Enzyme Inhibitors Isoenzymes Protein Isoforms Receptors, Estrogen Octoxynol rottlerin Luciferases Prkcd protein, rat PRKCD protein, human Protein Kinase C Protein Kinase C-delta Tetradecanoylphorbol Acetate
Topics	Acetophenones (pharmacology) Animals Benzopyrans (pharmacology) Blotting, Western Breast Neoplasms (drug therapy) Carcinogens Cell Division (drug effects) Cell Membrane (enzymology, metabolism) Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 Cyclins (biosynthesis) Cytosol (enzymology) Detergents (pharmacology) Dose-Response Relationship, Drug Enzyme Activation Enzyme Inhibitors (pharmacology) Humans Isoenzymes (physiology) Luciferases (metabolism) Octoxynol (pharmacology) Plasmids Protein Isoforms Protein Kinase C (physiology) Protein Kinase C-delta Rats Receptors, Estrogen (metabolism) Tetradecanoylphorbol Acetate Transfection Tumor Cells, Cultured

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