Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Breast Cancer Res Treat. 2010 Apr;120(2):357-67. doi: 10.1007/s10549-009-0393-2. Epub 2009 Apr 16.
To investigate a presumed crosstalk between estrogen receptor alpha (ERalpha) and the TGF-beta signaling pathway in breast cancer, we analyzed the TGF-beta-induced expression of the plasminogen activator inhibitor 1 (PAI-1) gene in ER-positive MCF-7 cells. After siRNA-mediated knock-down of endogenous ERalpha, the transcription level of PAI-1 was upregulated, pointing to an attenuation of TGF-beta signaling by the presence of ERalpha. We verified these findings by a vice versa approach using a primary ER-negative cell model transiently overexpressing either ERalpha or ERbeta. We found that ERalpha, but not ERbeta, led to a strong inhibition of the TGF-beta1 signal, monitored by TGF-beta reporter assays. This attenuation was completely independent of receptor stimulation by beta-estradiol (E2) or inhibition by the pure antagonist ICI 182.780 (ICI). Our results indicate a permanent repression of PAI-1 by ERalpha and suggest a ligand-independent crosstalk between ERalpha and TGF-beta signaling in breast cancer cells.
为了研究雌激素受体 α（ERα）与 TGF-β 信号通路之间假定的串扰在乳腺癌中的作用，我们分析了 TGF-β 诱导 ER 阳性 MCF-7 细胞中纤溶酶原激活物抑制剂 1（PAI-1）基因的表达。在 ERα 内源性敲低后，PAI-1 的转录水平上调，表明 ERα 存在时 TGF-β 信号受到抑制。我们通过使用瞬时过表达 ERα 或 ERβ 的原发性 ER 阴性细胞模型的相反方法验证了这些发现。我们发现 ERα，而不是 ERβ，通过 TGF-β 报告基因测定监测到 TGF-β1 信号的强烈抑制。这种衰减完全独立于β-雌二醇（E2）受体刺激或纯拮抗剂 ICI 182.780（ICI）的抑制。我们的结果表明 ERα 对 PAI-1 的持续抑制，并提示 ERα 和 TGF-β 信号通路在乳腺癌细胞中的配体非依赖性串扰。
