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

ABSTRACT: Estrogen receptor alpha (ER) is involved in cell growth and proliferation and functions as a transcription factor, a transcriptional coregulator, and in cytoplasmic signalling. The diverse roles of the ER include effects on e.g. bone, endometrium, ovaries, and mammary epithelium. The ER 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 functionally distinct ER isoforms have been described, but current transcript annotation in public databases is incomplete and inconsistent. We 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 to compare transcription factor activity, subcellular localisation, and response to the ER-targeting drug 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208238 | GEO | 2023/09/20

REPOSITORIES: GEO

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