Nagy Zsuzsanna, Jeselsohn Rinath
Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
Front Oncol. 2023 Jan 4;12:1037531. doi: 10.3389/fonc.2022.1037531. eCollection 2022.
Breast cancer is the most frequent female malignant tumor, and the leading cause of cancer death in women worldwide. The most common subtype of breast cancer is hormone receptor positive that expresses the estrogen receptor (ER). Targeting ER with endocrine therapy (ET) is the current standard of care for ER positive (ER+) breast cancer, reducing mortality by up to 40% in early- stage disease. However, resistance to ET represents a major clinical challenge for ER+ breast cancer patients leading to disease recurrence or progression of metastatic disease. Salient drivers of ET resistance are missense mutations in the ER gene () leading to constitutive transcriptional activity and reduced ET sensitivity. These mutations are particularly prominent and deleterious in metastatic breast cancer (MBC). In addition to activating point mutations, emerging evidence imposes that chromosomal translocation involving the gene can also drive ET resistance through the formation of chimeric transcription factors with constitutive transcriptional activity. Although these gene fusions are relatively rare, they are enriched in ET resistant metastatic disease. This review discusses the characteristics of ER fusion proteins and their association with clinical outcomes in more aggressive and metastatic breast cancer. The structure and classification of ER fusion proteins based on function and clinical significance are also addressed. Finally, this review summarizes the metastatic phenotypes exhibited by the ER fusion proteins and their role in intrinsic ET resistance.
乳腺癌是最常见的女性恶性肿瘤，也是全球女性癌症死亡的主要原因。乳腺癌最常见的亚型是表达雌激素受体（ER）的激素受体阳性型。以内分泌治疗（ET）靶向ER是ER阳性（ER+）乳腺癌目前的标准治疗方法，可使早期疾病的死亡率降低多达40%。然而，对ET的耐药性是ER+乳腺癌患者面临的一项重大临床挑战，会导致疾病复发或转移性疾病进展。ET耐药的主要驱动因素是ER基因中的错义突变，导致组成型转录活性并降低ET敏感性。这些突变在转移性乳腺癌（MBC）中尤为突出且有害。除了激活点突变外，新出现的证据表明，涉及该基因的染色体易位也可通过形成具有组成型转录活性的嵌合转录因子来驱动ET耐药。虽然这些基因融合相对罕见，但它们在ET耐药的转移性疾病中富集。本综述讨论了ER融合蛋白的特征及其与侵袭性更强和转移性乳腺癌临床结局的关联。还阐述了基于功能和临床意义的ER融合蛋白的结构和分类。最后，本综述总结了ER融合蛋白表现出的转移表型及其在内在ET耐药中的作用。
