文章：

内分泌反应性乳腺癌和对抗耐药性的策略

Endocrine-responsive breast cancer and strategies for combating resistance

原文发布日期：2002-02-01

DOI: 10.1038/nrc721

类型: Review Article

开放获取: 否

要点：

1. Breast cancer is the most common cancer of women in the western world. In most cases, breast cancer is oestrogen dependent, and treatment with oestrogen antagonists that inhibit oestrogen receptor (ER) action, particularly tamoxifen, has contributed to a dramatic reduction in breast cancer mortality. However, a substantial proportion of patients presenting with localized disease, and all of the patients with metastatic disease, become resistant to endocrine therapies.
2. In most cases, the ER is present in resistant tumours, and in many of these its activity continues to regulate tumour growth.
3. Resistance to endocrine therapy potentially arises by: ER activation in the absence of oestrogen; hypersensitivity of ER to low levels of circulating oestrogens; or ER activation, rather than inhibition, by oestrogen antagonists.
4. At the molecular level, mechanisms responsible for resistance include:
5. ER mutations that result in increased sensitivity to ligand and/or co-activator recruitment, and a resultant increase in ER activity.
6. Post-translational modifications that result in ligand-independent activation of the ER. These modifications can be triggered by the oncogenic activation of growth-factor signalling pathways.
7. Increased expression of the co-activator proteins that mediate ER activity. By contrast, downregulation of corepressor activity reduces the inhibitory potential of tamoxifen.
8. Mitogenic and anti-apoptotic effects can be mediated by non-genomic effects of the ER, through direct interaction with key components of several signal-transduction pathways. Altered activity of these pathways could contribute to resistance.
9. By understanding which of these pathways could be involved in mediating resistance, we might be able to develop strategies for overcoming or bypassing such resistance.

要点翻译：

1. 乳腺癌是西方世界女性最常见的恶性肿瘤。在大多数病例中，乳腺癌具有雌激素依赖性，采用抑制雌激素受体（ER）作用的雌激素拮抗剂（特别是他莫昔芬）进行治疗，显著降低了乳腺癌死亡率。然而，相当一部分局部病变患者和所有转移性病变患者最终都会产生内分泌治疗耐药性。
2. 在多数耐药肿瘤中仍存在雌激素受体，且其活性在多数情况下持续调控着肿瘤生长。内分泌治疗耐药性的产生可能源于：无雌激素状态下ER的激活；ER对低水平循环雌激素的超敏反应；或雌激素拮抗剂对ER的激活而非抑制。
3. 在分子层面，导致耐药性的机制包括：
   - ER突变导致对配体和/或共激活因子招募的敏感性增强，继而引起ER活性升高
   - 翻译后修饰导致ER不依赖配体的激活，这种修饰可由生长因子信号通路的致癌性激活触发
   - 介导ER活性的共激活蛋白表达增加。相反，共抑制因子活性下调会降低他莫昔芬的抑制潜能
   - ER通过非基因组效应与多种信号转导通路关键成分直接相互作用，可介导促有丝分裂和抗凋亡效应。这些通路活性的改变可能导致耐药性产生。
4. 通过解析这些通路中哪些可能参与介导耐药性，我们或能制定出克服或规避此类耐药性的策略。

英文摘要：

Deaths from breast cancer have fallen markedly over the past decade due, in part, to the use of endocrine agents that reduce the levels of circulating oestrogens or compete with oestrogen for binding to its receptor. However, many breast tumours either fail to respond or become resistant to endocrine therapies. By understanding the mechanisms that underlie this resistance, we might be able to develop strategies for overcoming or bypassing it.

摘要翻译： 

在过去十年中，乳腺癌的死亡人数显著下降，部分原因是使用了降低循环雌激素水平或与雌激素竞争结合其受体的内分泌药物。然而，许多乳腺肿瘤要么对治疗无反应，要么对内分泌治疗产生耐药性。通过理解这种耐药性的机制，我们可能能够开发出克服或绕过它的策略。

原文链接：

Endocrine-responsive breast cancer and strategies for combating resistance