de Pinho Inês Soares, Abreu Catarina, Gomes Inês, Casimiro Sandra, Pacheco Teresa Raquel, de Sousa Rita Teixeira, Costa Luís
Oncology Division, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisboa, Portugal.
Luis Costa Laboratory, Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
Explor Target Antitumor Ther. 2022;3(3):337-361. doi: 10.37349/etat.2022.00086. Epub 2022 Jun 20.
The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER), progesterone receptor-positive (PR), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.
最常见的乳腺癌（BC）亚型是激素依赖性的，即雌激素受体阳性（ER）、孕激素受体阳性（PR）或两者皆阳性，这些共同构成了管腔亚型。管腔型BC的主要治疗方法是内分泌治疗（ET），其中包括几种直接作用于ER或抑制雌激素产生的药物。多年来，ET已被证明在降低转移性和非转移性BC的死亡率以及改善临床结局方面具有疗效。然而，ET耐药性的出现促进了癌症的存活和进展，并阻碍了内分泌药物的使用。目前，与内分泌耐药相关的几种机制已得到广泛研究。基于当前的临床和临床前数据，本文简要回顾了已明确的ET耐药途径，并继续聚焦于最近发现的三种可能介导ET耐药的途径，即核因子κB受体活化因子配体（RANKL）/核因子κB受体活化因子（RANK）、核因子κB（NFκB）和Notch。此外，本文概述了批准联合疗法克服BC中ET耐药性的证据，同时强调了未来研究聚焦于ET耐药性假定介质以发现该疾病新治疗选择的相关性。
