DeNardo David G, Cuba Valerie L, Kim HeeTae, Wu Kendall, Lee Adrian V, Brown Powel H
Department of Molecular and Cellular Biology, and Breast Center, Baylor College of Medicine, Houston, TX, USA.
Mol Cell Endocrinol. 2007 Oct 15;277(1-2):13-25. doi: 10.1016/j.mce.2007.07.006. Epub 2007 Jul 19.
In this study, we determined whether ER DNA binding is necessary for estrogen to stimulate the growth of breast cancer cells. To investigate the requirement of ER DNA binding we expressed either wild-type or a DNA-binding mutant ERalpha in a clone of the MCF-7 breast cancer cell line that no longer expressed endogenous ERalpha. Estrogen did not activate non-genomic kinase cascades in the parental MCF-7 cells or in cells expressing ERalpha mutant. In cells expressing the ERalpha mutant, estrogen did not induce ERE-dependent gene expression but did induce AP-1- and Sp1-dependent gene expression and the cell cycle regulatory genes cyclin D1 and c-myc. However, we demonstrated that estrogen still induced cell proliferation in MCF-7 cells expressing the ERalpha mutant. These results demonstrate that ER DNA binding is not absolutely required for estrogen to induce breast cancer cell growth.
在本研究中，我们确定雌激素刺激乳腺癌细胞生长是否需要雌激素受体（ER）与DNA结合。为了研究ER与DNA结合的必要性，我们在不再表达内源性ERα的MCF-7乳腺癌细胞系克隆中表达野生型或DNA结合突变型ERα。雌激素在亲本MCF-7细胞或表达ERα突变体的细胞中未激活非基因组激酶级联反应。在表达ERα突变体的细胞中，雌激素未诱导雌激素反应元件（ERE）依赖性基因表达，但诱导了激活蛋白-1（AP-1）和特异性蛋白1（Sp1）依赖性基因表达以及细胞周期调节基因细胞周期蛋白D1和原癌基因c-myc。然而，我们证明雌激素仍能诱导表达ERα突变体的MCF-7细胞增殖。这些结果表明，雌激素诱导乳腺癌细胞生长并非绝对需要ER与DNA结合。
