雌激素受体α（ER）参与细胞生长和增殖，发挥转录因子、转录共调节因子和细胞质信号传导的功能。它影响骨骼、子宫内膜、卵巢和乳腺上皮等。在乳腺癌的临床管理中，ER是一个关键的生物标志物，被用作预后和治疗预测因素以及治疗靶点。已经描述了几种ER亚型，但公共数据库中的转录注释不完整且不一致，并且功能差异尚不清楚。我们分析了乳腺肿瘤、乳腺癌细胞系和正常组织的短读长和长读长RNA测序数据，创建了ER转录本的综合注释，并将其与全长蛋白和六种可选亚型的实验研究相结合。这些亚型具有不同的转录因子活性、亚细胞定位和对于针对ER的药物他莫昔芬和富马酮的反应。抗体在检测可选亚型上存在差异，这对于常规病理学中ER状态的解释引起了关注。未来的工作应研究可选亚型对患者生存和治疗反应的影响。准确注释ER亚型将有助于临床数据的解释，并为改善对ER在健康和疾病中的理解的功能研究提供信息。© 2023 The Authors. 版权所有：John Wiley & Sons Ltd发表的《癌症医学》。

Oestrogen receptor alpha (ER) is involved in cell growth and proliferation and functions as a transcription factor, a transcriptional coregulator, and in cytoplasmic signalling. It affects, for example, bone, endometrium, ovaries and mammary epithelium. It is a key biomarker in clinical management of breast cancer, where it is used as a prognostic and treatment-predictive factor, and a therapeutical target. Several ER isoforms have been described, but transcript annotation in public databases is incomplete and inconsistent, and functional differences are not well understood.We have analysed short- and long-read RNA sequencing data from breast tumours, breast cancer cell lines, and normal tissues to create a comprehensive annotation of ER transcripts and combined it with experimental studies of full-length protein and six alternative isoforms.The isoforms have varying transcription factor activity, subcellular localisation, and response to the ER-targeting drugs tamoxifen and fulvestrant. Antibodies differ in ability to detect alternative isoforms, which raises concerns for the interpretation of ER-status in routine pathology.Future work should investigate the effects of alternative isoforms on patient survival and therapy response. An accurate annotation of ER isoforms will aid in interpretation of clinical data and inform functional studies to improve our understanding of the ER in health and disease.© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.