Constitutive MEK/MAPK activation leads to p27(Kip1) deregulation and antiestrogen resistance in human breast cancer cells.
Antiestrogens, such as the drug tamoxifen, inhibit breast cancer growth by inducing cell cycle arrest. Antiestrogens require action of the cell cycle inhibitor p27(Kip1) to mediate G1 arrest in estrogen receptor-positive breast cancer cells. We report that constitutive activation of the mitogen-activated protein kinase (MAPK) pathway alters p27 phosphorylation, reduces p27 protein levels, reduces the cdk2 inhibitory activity of the remaining p27, and contributes to antiestrogen resistance. In two antiestrogen-resistant cell lines that showed increased MAPK activation, inhibition of the MAPK kinase (MEK) by addition of U0126 changed p27 phosphorylation and restored p27 inhibitory function and sensitivity to antiestrogens. Using antisense p27 oligonucleotides, we demonstrated that this restoration of antiestrogen-mediated cell cycle arrest required p27 function. These data suggest that oncogene-mediated MAPK activation, frequently observed in human breast cancers, contributes to antiestrogen resistance through p27 deregulation.
Donovan
J C
JC
Molecular and Cell Biology, Sunnybrook and Women's College Health Science Centre, Toronto, Ontario M4N 3M5, Canada.
Milic
A
A
Slingerland
J M
JM
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D020847:Estrogen Receptor Modulators; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020928:Mitogen-Activated Protein Kinases