Brinkman Joeli A, El-Ashry Dorraya
University of Miami, Miller School of Medicine, Department of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):67-78. doi: 10.1007/s10911-009-9113-0. Epub 2009 Mar 5.
Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ERalpha in breast cancers is an important prognostic indicator. About 30-40% of breast cancers lack detectable ERalpha protein. ERalpha- breast cancers are resistant to endocrine therapies and have a worse prognosis than ERalpha+ breast cancers. Since expression of ERalpha is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ERalpha- phenotype and develop interventions to restore ERalpha expression in ERalpha- breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ERalpha expression and in these cases; demethylation of the ERalpha promoter or treatment with HDAC inhibitors shows promise in restoring ERalpha expression in ERalpha- breast cancers. Two additional potential mechanisms underlying generation of the ERalpha- phenotype involve E6-AP and Src, both of which have been shown to be elevated in ERalpha- breast cancer and can drive the proteasomal degradation of ERalpha. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ERalpha- phenotype and that inhibition of MAPK activity can cause re-expression of the ERalpha and restore sensitivity to endocrine therapies. Given the challenges in treating ERalpha- breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ERalpha are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ERalpha- breast cancers.
在西方化世界中，乳腺癌是女性癌症的主要病因。乳腺癌中雌激素受体α（ERα）的有无是一个重要的预后指标。约30%-40%的乳腺癌检测不到ERα蛋白。ERα阴性乳腺癌对内分泌治疗耐药，且预后比ERα阳性乳腺癌更差。由于ERα的表达是对内分泌治疗产生反应所必需的，目前正在进行研究以了解ERα阴性表型的产生机制，并开发干预措施来恢复ERα阴性乳腺癌中ERα的表达。DNA甲基化和染色质重塑是两种与ERα表达缺失相关的表观遗传机制，在这些情况下，ERα启动子的去甲基化或用组蛋白去乙酰化酶（HDAC）抑制剂治疗有望恢复ERα阴性乳腺癌中ERα的表达。ERα阴性表型产生的另外两种潜在机制涉及E6-AP和Src，这两种蛋白在ERα阴性乳腺癌中均被证明表达升高，并且可以驱动ERα的蛋白酶体降解。最近，研究表明，由于丝裂原活化蛋白激酶（MAPK）活性过高导致的生长因子信号上调显著促成了ERα阴性表型的产生，抑制MAPK活性可导致ERα重新表达并恢复对内分泌治疗的敏感性。鉴于治疗ERα阴性乳腺癌面临的挑战，了解和调控影响ERα表达的细胞机制对于恢复对内分泌治疗的敏感性以及设计治疗ERα阴性乳腺癌的新型疗法至关重要。
