Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Room 145, Baltimore, MD 21231, USA.
Carcinogenesis. 2012 Apr;33(4):918-30. doi: 10.1093/carcin/bgs105. Epub 2012 Feb 16.
Understanding the molecular pathways that contribute to the development of tamoxifen resistance is a critical research priority as acquired tamoxifen resistance is the principal cause of poor prognosis and death of patients with originally good prognosis hormone-responsive breast tumors. In this report, we provide evidence that Med1, an important subunit of mediator coactivator complex, is spontaneously upregulated during acquired tamoxifen-resistance development potentiating agonist activities of tamoxifen. Phosphorylated Med1 and estrogen receptor (ER) are abundant in tamoxifen-resistant breast cancer cells due to persistent activation of extracellular signal-regulated kinases. Mechanistically, phosphorylated Med1 exhibits nuclear accumulation, increased interaction with ER and higher tamoxifen-induced recruitment to ER-responsive promoters, which is abrogated by inhibition of Med1 phosphorylation. Stable knockdown of Med1 in tamoxifen-resistant cells not only reverses tamoxifen resistance in vitro but also in vivo. Finally, higher expression levels of Med1 in the tumor significantly correlated with tamoxifen resistance in ER-positive breast cancer patients on adjuvant tamoxifen monotherapy. In silico analysis of breast cancer, utilizing published profiling studies showed that Med1 is overexpressed in aggressive subsets. These findings provide what we believe is the first evidence for a critical role for Med1 in tamoxifen resistance and identify this coactivator protein as an essential effector of the tamoxifen-induced breast cancer growth.
了解导致他莫昔芬耐药的分子途径是一项关键的研究重点，因为获得性他莫昔芬耐药是原本预后良好的激素反应性乳腺癌患者预后不良和死亡的主要原因。在本报告中，我们提供的证据表明，中介共激活复合物的重要亚基 Med1 在获得性他莫昔芬耐药发展过程中自发上调，增强了他莫昔芬的激动剂活性。由于细胞外信号调节激酶的持续激活，磷酸化 Med1 和雌激素受体 (ER) 在他莫昔芬耐药乳腺癌细胞中大量存在。从机制上讲，磷酸化 Med1 表现出核积累，与 ER 的相互作用增加，以及更高的他莫昔芬诱导的与 ER 反应性启动子的募集，这一过程可被 Med1 磷酸化抑制所阻断。在他莫昔芬耐药细胞中稳定敲低 Med1 不仅可逆转体外他莫昔芬耐药，还可逆转体内他莫昔芬耐药。最后，肿瘤中 Med1 的高表达水平与接受辅助他莫昔芬单药治疗的 ER 阳性乳腺癌患者的他莫昔芬耐药显著相关。利用已发表的基因表达谱研究进行的乳腺癌计算机分析显示，Med1 在侵袭性亚群中过度表达。这些发现为 Med1 在他莫昔芬耐药中的关键作用提供了我们认为是首个证据，并将该共激活蛋白鉴定为他莫昔芬诱导的乳腺癌生长的必需效应因子。
