Yu K, Toral-Barza L, Discafani C, Zhang W G, Skotnicki J, Frost P, Gibbons J J
Wyeth-Ayerst Research, Department of Oncology, 401 North Middletown Road, Pearl River, New York 10965, USA.
Endocr Relat Cancer. 2001 Sep;8(3):249-58. doi: 10.1677/erc.0.0080249.
The mammalian target of rapamycin (mTOR) is a central regulator of G1 cell cycle protein synthesis that precedes commitment to normal cellular replication. We have studied the effect of cell cycle inhibitor-779 (CCI-779), a rapamycin ester that inhibits mTOR function, on the proliferation of a panel of breast cancer cell lines. Six of eight lines studied were sensitive (IC(50)< or = 50 nM) and two lines were resistant (IC(50)>1.0 microM) to CCI-779. Sensitive lines were estrogen dependent (MCF-7, BT-474, T-47D), or lacked expression of the tumor suppressor PTEN (MDA-MB-468, BT-549), and/or overexpressed the Her-2/neu oncogene (SKBR-3, BT-474). Resistant lines (MDA-MB-435, MDA-MB-231) shared none of these properties. CCI-779 (50 nM) inhibited mTOR function in both a sensitive and a resistant line. In nu/nu mouse xenografts, CCI-779 inhibited growth of MDA-MB-468 (sensitive) but not MDA-MB-435 resistant tumors. Treatment of sensitive lines with CCI-779 resulted in a decrease in D-type cyclin and c-myc levels and an increase in p27(kip-1) levels. There was good correlation between activation of the Akt pathway and sensitivity to CCI-779. Amplification of mTOR-regulated p70S6 kinase, which is downstream of Akt, may also have conferred CCI-779 sensitivity to MCF-7 cells. Taken together, the data suggest that mTOR may be a good target for breast cancer therapy, especially in tumors with Akt activation resulting from either growth factor dependency or loss of PTEN function.
雷帕霉素哺乳动物靶点（mTOR）是G1期细胞周期蛋白合成的核心调节因子，先于正常细胞复制的启动。我们研究了细胞周期抑制剂-779（CCI-779），一种抑制mTOR功能的雷帕霉素酯，对一组乳腺癌细胞系增殖的影响。所研究的8个细胞系中有6个对CCI-779敏感（半数抑制浓度[IC(50)]≤50 nM），2个细胞系耐药（IC(50)>1.0 μM）。敏感细胞系为雌激素依赖型（MCF-7、BT-474、T-47D），或缺乏肿瘤抑制因子PTEN的表达（MDA-MB-468、BT-549），和/或过表达Her-2/neu癌基因（SKBR-3、BT-474）。耐药细胞系（MDA-MB-435、MDA-MB-231）不具备这些特性。CCI-779（50 nM）在敏感和耐药细胞系中均抑制mTOR功能。在无胸腺裸鼠异种移植瘤中，CCI-779抑制MDA-MB-468（敏感）肿瘤的生长，但不抑制MDA-MB-435耐药肿瘤的生长。用CCI-779处理敏感细胞系导致D型细胞周期蛋白和c-myc水平降低，p27(kip-1)水平升高。Akt信号通路的激活与对CCI-779的敏感性之间存在良好的相关性。mTOR调节的p70S6激酶（Akt下游）的扩增也可能赋予MCF-7细胞对CCI-779的敏感性。综上所述，数据表明mTOR可能是乳腺癌治疗的一个良好靶点，尤其是在因生长因子依赖性或PTEN功能丧失而导致Akt激活的肿瘤中。
