Teixeira C, Reed J C, Pratt M A
Department of Pharmacology, University of Ottawa, Ontario, Canada.
Cancer Res. 1995 Sep 1;55(17):3902-7.
Recent studies have shown that the Bcl-2 protein suppresses programmed cell death or apoptosis induced by a variety of stimuli including chemotherapeutic drugs. Because estrogen promotes the survival of estrogen-dependent breast cancer cells in vivo, we investigated whether estrogen might regulate levels of Bcl-2 gene expression in an estrogen-responsive human breast cancer cell line. Estrogen receptor-positive MCF-7 human breast cancer cells cultured in the presence of estrogen express the 8.5-kb Bcl-2 mRNA transcript. Depletion of estrogen from the medium results in loss of expression of the mRNA, whereas reexposure to estrogen markedly induces the Bcl-2 transcript. The changes in Bcl-2 mRNA are paralleled by changes in Bcl-2 protein levels. Estrogen-induced increases in Bcl-2 are significantly inhibited by inclusion of the pure antiestrogen ICI 164,384 in the medium. The Bax protein that heterodimerizes with Bcl-2 and promotes cell death is expressed in MCF-7 cells grown in the presence of estrogen and is unaffected by culture in estrogen-free medium. Estrogen depletion doubles the sensitivity of MCF-7 cells to the cytotoxic effects of Adriamycin compared with cells cultured in medium supplemented with estrogen, consistent with a decrease in the Bcl-2 levels. MCF-7 cells treated simultaneously with estrogen and ICI 164,384 exhibit markedly lower resistance to Adriamycin compared with cells treated with estrogen alone. In the absence of estrogen, MCF-7 cells transfected with Bcl-2 expression plasmids display a marked increase in resistance to Adriamycin. In the presence of estrogen, MCF-7 cells expressing Bcl-2 antisense transcripts are rendered twice as sensitive to acute Adriamycin cytotoxicity as a control clone. We conclude that estrogen can promote resistance of estrogen receptor bearing human breast cancer cells to chemotherapeutic drugs through a mechanism that involves regulation of the Bcl-2 proto-oncogene.
最近的研究表明，Bcl-2蛋白可抑制由包括化疗药物在内的多种刺激所诱导的程序性细胞死亡或凋亡。由于雌激素可促进雌激素依赖的乳腺癌细胞在体内存活，我们研究了雌激素是否可能调节雌激素反应性人乳腺癌细胞系中Bcl-2基因的表达水平。在雌激素存在下培养的雌激素受体阳性MCF-7人乳腺癌细胞表达8.5 kb的Bcl-2 mRNA转录本。从培养基中去除雌激素会导致该mRNA表达丧失，而重新暴露于雌激素会显著诱导Bcl-2转录本。Bcl-2 mRNA的变化与Bcl-2蛋白水平的变化平行。培养基中加入纯抗雌激素ICI 164,384可显著抑制雌激素诱导的Bcl-2增加。与Bcl-2异二聚化并促进细胞死亡的Bax蛋白在雌激素存在下生长的MCF-7细胞中表达，且不受无雌激素培养基培养的影响。与在补充雌激素的培养基中培养的细胞相比，去除雌激素使MCF-7细胞对阿霉素细胞毒性的敏感性增加一倍，这与Bcl-2水平降低一致。与单独用雌激素处理的细胞相比，同时用雌激素和ICI 164,384处理的MCF-7细胞对阿霉素的抗性明显降低。在无雌激素的情况下，用Bcl-2表达质粒转染的MCF-7细胞对阿霉素的抗性显著增加。在雌激素存在下，表达Bcl-2反义转录本的MCF-7细胞对急性阿霉素细胞毒性的敏感性是对照克隆的两倍。我们得出结论，雌激素可通过涉及调节Bcl-2原癌基因的机制促进雌激素受体阳性人乳腺癌细胞对化疗药物的抗性。
