Alternative promoters and splicing create multiple functionally distinct isoforms of oestrogen receptor alpha in breast cancer and healthy tissues

• Published in: Cancer medicine (Malden, MA) MA), 2023-09, Vol.12 (18), p.18931-18945
• Main Authors: Balcazar Lopez, Carlos Enrique, Albrecht, Juliane, Hafstað, Völundur, Börjesson Freitag, Cornelia, Vallon‐Christersson, Johan, Bellodi, Cristian, Persson, Helena
• Format: Article
• Language: English
• Subjects: Alternative splicing; Annotations; Antibodies; Biomarkers; Breast cancer; Cancer and Oncology; Cancer och onkologi; Clinical Medicine; Cloning; Data analysis; Drug delivery; Endometrium; Epithelium; Estrogen receptors; Fulvestrant; Isoforms; Klinisk medicin; Ligands; Medical and Health Sciences; Medicin och hälsovetenskap; oestrogen receptor; Phenols; Proteins; Transcription factors; Tumor cell lines; Tumors
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.6508

Background 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. Methods 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. Results 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. Conclusions 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. A comprehensive transcript annotation for the breast cancer therapy target oestrogen receptor alpha including alternative first, internal and last exons, as well as splice donor and acceptor sites. Detailed functional studies compare six alternative isoforms to the full‐length protein.