Estrogen receptor mutations and changes in downstream gene expression and signaling.
Estrogen receptor mutations and changes in downstream gene expression and signaling.
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DOI：
10.1158/1078-0432.ccr-09-1753
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发表时间：
2010-05-15
期刊：
影响因子：
--
通讯作者：
Fuqua SA
中科院分区：
文献类型：
--
作者：
Barone I;Brusco L;Fuqua SA
雌激素在调节乳腺癌的生长和分化中起着至关重要的作用，大约三分之二的乳腺肿瘤表达雌激素受体α（ERα）。因此，通过使用抗雌激素（如他莫昔芬）抑制ERα作用或通过使用芳香酶抑制剂（AI）（如来曲唑、阿那曲唑或阿司美坦）降低雌激素水平的治疗策略是为ERα阳性癌症女性提供的标准治疗。然而，并非所有患者都对内分泌治疗有反应（称为从头耐药），并且大量有反应的患者最终会在治疗期间发生疾病进展或复发（获得性耐药）。最近已经鉴定了由于选择性剪接或基因突变引起的受体的变体形式。本文综述了这些变异受体及其在抵抗内分泌治疗中的临床意义，通过解决它们与生长因子受体和信号传导成分的分子串扰。了解受体介导的信号传导的复杂性，有希望为新的组合治疗方案，重点是更有效地阻断受体串扰。
Estrogens play a crucial role in regulating the growth and differentiation of breast cancers, with approximately two-thirds of all breast tumours expressing the estrogen receptor alpha (ERα). Therefore, therapeutic strategies directed at inhibiting the action of ERα by using antiestrogens such as tamoxifen, or reducing estrogens levels by using aromatase inhibitors (AIs), such as letrozole, anastrozole, or exemestane, are the standard treatments offered to women with ERα-positive cancer. However, not all patients respond to endocrine therapies (termed de novo resistance), and a large number of patients who do respond will eventually develop disease progression or recurrence while on therapy (acquired resistance). Recently variant forms of the receptor due to alternative splicing or gene mutation have been identified. This article reviews these variant receptors and their clinical relevance in resistance to endocrine therapy, by addressing their molecular cross-talk with growth factor receptors and signaling components. Understanding the complexity of receptor-mediated signaling has promise for new combined therapeutic options which focus on more efficient blockade of receptor cross-talk.