Donovan J C, Milic A, Slingerland J M
Molecular and Cell Biology, Sunnybrook and Women's College Health Science Centre, Toronto, Ontario M4N 3M5, Canada.
J Biol Chem. 2001 Nov 2;276(44):40888-95. doi: 10.1074/jbc.M106448200. Epub 2001 Aug 29.
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.
抗雌激素药物，如他莫昔芬，通过诱导细胞周期停滞来抑制乳腺癌生长。抗雌激素需要细胞周期抑制剂p27（Kip1）发挥作用，以介导雌激素受体阳性乳腺癌细胞中的G1期停滞。我们报告称，丝裂原活化蛋白激酶（MAPK）途径的组成性激活会改变p27的磷酸化，降低p27蛋白水平，降低剩余p27的cdk2抑制活性，并导致抗雌激素耐药。在两个显示MAPK激活增加的抗雌激素耐药细胞系中，添加U0126抑制丝裂原活化蛋白激酶激酶（MEK）可改变p27磷酸化，并恢复p27抑制功能和对抗雌激素的敏感性。使用反义p27寡核苷酸，我们证明抗雌激素介导的细胞周期停滞的这种恢复需要p27的功能。这些数据表明，在人类乳腺癌中经常观察到的癌基因介导的MAPK激活，通过p27失调导致抗雌激素耐药。
