Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile.
Horm Cancer. 2010 Jun;1(3):117-26. doi: 10.1007/s12672-010-0019-5.
2-Methoxyestradiol (2ME) is an endogenous metabolite of 17β-estradiol with antiangiogenic and antitumor properties, although its mechanisms of action remain unclear. Progestins in hormone replacement therapy increase the risk of breast cancer. Progesterone also enhances the procoagulant activity and invasive potential of progesterone receptor (PR)-positive breast cancer cell lines, an effect largely mediated by induction of tissue factor (TF), the cellular activator of the coagulation cascade. Here we show that 2ME abrogates the induction TF expression in progesterone-treated breast cancer cells via a mechanism that does not involve the estrogen receptor. Instead, we demonstrate that by selectively antagonizing ERK1/2 signaling in breast cancer cells, 2ME limits the transactivation potential of ligand-bound PR and inhibits the expression of endogenous progesterone targets, such as TF and signal transducer and activator of transcription 5. We further demonstrate that 2ME can alter the phosphorylation status of PR. Thus, 2ME prevents progesterone-dependent increase in breast cancer cell invasiveness and procoagulant activity by uncoupling PR from the ERK1/2 signal transduction pathway.
2-甲氧基雌二醇（2ME）是 17β-雌二醇的内源性代谢物，具有抗血管生成和抗肿瘤特性，但其作用机制尚不清楚。激素替代疗法中的孕激素会增加乳腺癌的风险。孕激素还增强孕激素受体（PR）阳性乳腺癌细胞系的促凝活性和侵袭潜能，这种作用主要通过诱导组织因子（TF）来介导，TF 是凝血级联反应的细胞激活剂。在这里，我们表明 2ME 通过不涉及雌激素受体的机制阻断孕激素处理的乳腺癌细胞中 TF 的诱导表达。相反，我们证明通过选择性拮抗乳腺癌细胞中的 ERK1/2 信号，2ME 限制配体结合的 PR 的反式激活潜力并抑制内源性孕激素靶标（如 TF 和信号转导和转录激活因子 5）的表达。我们进一步证明 2ME 可以改变 PR 的磷酸化状态。因此，2ME 通过将 PR 与 ERK1/2 信号转导途径解偶联，防止孕激素依赖性增加乳腺癌细胞的侵袭性和促凝活性。
