文章：

乳腺癌内分泌抵抗的生物学决定因素

Biological determinants of endocrine resistance in breast cancer

原文发布日期：2009-09-01

DOI: 10.1038/nrc2713

类型: Review Article

开放获取: 否

要点：

1. Endocrine therapies that target oestrogen action (anti-oestrogens and aromatase inhibitors) are widely used and successful breast cancer therapies, but many women treated with these therapies will relapse with endocrine-resistant disease.
2. Mechanisms of endocrine resistance in oestrogen receptor (ER)-positive breast cancers include loss of ERα expression and expression of truncated isoforms of ERα and ERβ, post-translational modifications of ERα, increased AP1 activity and deregulation of ER co-activators, increased receptor tyrosine kinase signalling leading to the activation of the Erk and PI3K pathways, and deregulation of the cell cycle and apoptotic machinery.
3. Gene expression signatures that are predictive of poor outcome in women treated with tamoxifen commonly contain ER target genes, as well as genes involved in proliferation, apoptosis, and invasion and metastasis. Many of these signatures are also predictive of outcome in women who have not been treated with tamoxifen and so are markers of intrinsic biology rather than specific to tamoxifen responsiveness.
4. Gene expression signatures representing particular biological processes (for example, cell cycle progression, cell death and invasion) or pathways (for example, RB deregulation, MYC overexpression and E2f activation) can also predict outcome in women treated with tamoxifen and point towards possible mechanisms for endocrine resistance.
5. Functional genetic screens have successfully identified several genes, the loss or overexpression of which can reduce anti-oestrogen sensitivity in cell lines and is associated with clinical endocrine resistance.
6. Insights into the mechanisms of resistance have suggested possible therapeutic approaches for endocrine-resistant ER-positive breast cancer, for example tyrosine kinase inhibitors. Further potential therapeutic targets may emerge from combining large-scale genomic and transcriptomic data with large-scale functional analyses.

要点翻译：

1. 针对雌激素作用的内分泌疗法（抗雌激素药物和芳香酶抑制剂）是广泛应用且成功的乳腺癌治疗方法，但许多接受这些疗法的患者会因产生内分泌耐药性而复发。
2. 雌激素受体阳性乳腺癌的内分泌耐药机制包括：ERα表达缺失、ERα和ERβ截短亚型的表达、ERα的翻译后修饰、AP1活性增强与ER共激活因子失调、受体酪氨酸激酶信号传导增强导致Erk和PI3K通路激活，以及细胞周期和凋亡机制失调。
3. 在他莫昔芬治疗患者中预测不良预后的基因表达特征通常包含ER靶基因，以及参与增殖、凋亡、侵袭和转移的基因。这些特征多数也能预测未接受他莫昔芬治疗患者的预后，因此属于内在生物学标志，而非他莫昔芬特异性反应指标。
4. 代表特定生物过程（如细胞周期进程、细胞死亡和侵袭）或通路（如RB失调、MYC过表达和E2f激活）的基因表达特征同样能预测他莫昔芬治疗患者的预后，并提示潜在的内分泌耐药机制。
5. 功能性遗传筛选已成功鉴定出多个基因，这些基因的缺失或过表达会降低细胞系对抗雌激素的敏感性，并与临床内分泌耐药相关。
6. 对耐药机制的深入认识为ER阳性内分泌耐药乳腺癌提出了潜在治疗策略（如酪氨酸激酶抑制剂）。通过将大规模基因组学、转录组数据与功能性分析相结合，可能会发现更多潜在治疗靶点。

英文摘要：

Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance. However, definition of the specific genetic lesions and molecular processes that determine clinical endocrine resistance is incomplete. The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.

摘要翻译： 

靶向雌激素作用的内分泌治疗（如抗雌激素药物他莫昔芬和芳香化酶抑制剂）可降低乳腺癌死亡率，但其疗效受内在性和获得性治疗耐药的限制。他莫昔芬反应的候选分子生物标志物和基因表达特征强调，增殖和存活信号失调在内分泌耐药中的重要性。然而，决定临床内分泌耐药的具体遗传病变和分子过程尚未完全明确。大规模计算和遗传学方法的发展，有望识别内分泌耐药的中介因子，这些因子可作为潜在治疗靶点和临床反应的生物标志物加以利用。

原文链接：

Biological determinants of endocrine resistance in breast cancer