Constitutive MEK/MAPK Activation Leads to p27Kip1Deregulation and Antiestrogen Resistance in Human Breast Cancer Cells
作者： Jeffrey C. H. Donovan , Andrea Milic , Joyce M. Slingerland
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摘要: Antiestrogens, such as the drug tamoxifen, inhibit breast cancer growth by inducing cell cycle arrest. Antiestrogens require action of inhibitor p27Kip1 to mediate G1 arrest in estrogen receptor-positive cells. We report that constitutive activation mitogen-activated protein kinase (MAPK) pathway alters p27 phosphorylation, reduces levels, cdk2 inhibitory activity remaining p27, and contributes antiestrogen resistance. In two antiestrogen-resistant lines showed increased MAPK activation, inhibition (MEK) addition U0126 changed phosphorylation restored function sensitivity antiestrogens. Using antisense oligonucleotides, we demonstrated this restoration antiestrogen-mediated required function. These data suggest oncogene-mediated frequently observed human cancers, resistance through deregulation.
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