Clarke Robert, Tyson John J, Dixon J Michael
Department of Oncology, Georgetown University Medical Center, Washington DC 20057, USA.
Department of Biological Sciences, Virginia Polytechnic and State University, Blacksburg, VA 24061, USA.
Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3(0 3):220-34. doi: 10.1016/j.mce.2015.09.035. Epub 2015 Oct 9.
Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects.
表达可检测水平的ESR1基因（雌激素受体α；ERα）产物的肿瘤是乳腺癌中最大的单一分子亚型。最终死于ERα阳性乳腺癌的女性比死于HER2阳性疾病（其中几乎一半也表达ERα）和/或三阴性乳腺癌（ERα阴性、孕激素受体阴性和HER2阴性）的女性更多。抗雌激素药物和芳香化酶抑制剂在改善总体生存率方面的能力基本无法区分，几乎50%的ERα阳性乳腺癌最终会对这些内分泌治疗中的一种或多种产生耐药。这些疗法在ERα阳性乳腺癌中失败的确切原因在很大程度上仍不清楚。他莫昔芬耐药的药物遗传学解释存在争议。ERα突变在内分泌耐药中的作用仍不清楚。事实证明，针对与内分泌耐药最密切相关的生长因子和癌基因，在大幅提高总体生存率方面，尤其是在转移性情况下，大多令人失望。尽管如此，内分泌耐药方面出现了一些新的概念，这些概念整合了分子信号传导、细胞代谢和应激反应，包括内质网应激和未折叠蛋白反应（UPR），提供了新的见解并提出了创新的治疗靶点。有令人鼓舞的证据表明，与CDK4/CDK6抑制剂联合用药可以延长无复发生存期，这可能最终转化为总体生存率的提高。免疫疗法在其他癌症中所见到的改善是否能在乳腺癌中实现，尤其是在ERα阳性乳腺癌中，仍有待确定。本综述探讨了内分泌治疗耐药的基本机制，最后从系统生物学方法中得出一些新的见解，进一步详细阐述了自噬和未折叠蛋白反应，并简要讨论了令人兴奋的新途径和未来前景。
