Saxena Neeraj K, Sharma Dipali
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
Mol Cell Pharmacol. 2010;2(5):191-202.
Breast tumors expressing estrogen receptor alpha (ER) respond well to therapeutic strategies using SERMs (selective estrogen receptor modulators) such as tamoxifen. However, about thirty percent of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents and histone deacetylase inhibitors leads to expression of ER mRNA and functional protein. Additionally, growth factor signaling pathways have also been implicated in ER silencing in ER-negative tumor phenotype. Recently, important role of components of ubiquitin-proteasome pathway has been shown in mediating downregulation of ER. In this article, we will review various mechanisms underlying the silencing of ER in ER negative tumor phenotype and discuss diverse strategies to combat it. Ongoing studies may provide the mechanistic insight to design therapeutic strategies directed towards epigenetic and non-epigenetic mechanisms in the prevention or treatment of ER-negative breast cancer.
表达雌激素受体α（ER）的乳腺肿瘤对使用他莫昔芬等选择性雌激素受体调节剂（SERM）的治疗策略反应良好。然而，约30%的浸润性乳腺癌是激素非依赖性的，因为它们由于ER启动子的高甲基化而缺乏ER表达。用去甲基化剂和组蛋白脱乙酰酶抑制剂处理ER阴性乳腺癌细胞会导致ER mRNA和功能性蛋白的表达。此外，生长因子信号通路也与ER阴性肿瘤表型中ER的沉默有关。最近，泛素-蛋白酶体途径的成分在介导ER的下调中显示出重要作用。在本文中，我们将综述ER阴性肿瘤表型中ER沉默的各种潜在机制，并讨论对抗它的不同策略。正在进行的研究可能会为设计针对表观遗传和非表观遗传机制的治疗策略提供机制性见解，以预防或治疗ER阴性乳腺癌。
