Alternative promoters and splicing create multiple functionally distinct isoforms of oestrogen receptor alpha in breast cancer and healthy tissues
(2023) In Cancer Medicine 12(18). p.18931-18945- Abstract
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... (More)
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.
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- author
- Balcazar Lopez, Carlos Enrique LU ; Albrecht, Juliane LU ; Hafstað, Völundur LU ; Börjesson Freitag, Cornelia LU ; Vallon-Christersson, Johan LU ; Bellodi, Cristian LU and Persson, Helena LU
- organization
- publishing date
- 2023-09-07
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Medicine
- volume
- 12
- issue
- 18
- pages
- 18931 - 18945
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:85170571957
- pmid:37676103
- ISSN
- 2045-7634
- DOI
- 10.1002/cam4.6508
- language
- English
- LU publication?
- yes
- additional info
- © 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
- id
- 857210a4-0e17-4245-889a-21bdcc6a1ab0
- date added to LUP
- 2023-09-08 10:20:08
- date last changed
- 2024-04-23 19:36:06
@article{857210a4-0e17-4245-889a-21bdcc6a1ab0, abstract = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}}, author = {{Balcazar Lopez, Carlos Enrique and Albrecht, Juliane and Hafstað, Völundur and Börjesson Freitag, Cornelia and Vallon-Christersson, Johan and Bellodi, Cristian and Persson, Helena}}, issn = {{2045-7634}}, language = {{eng}}, month = {{09}}, number = {{18}}, pages = {{18931--18945}}, publisher = {{Wiley-Blackwell}}, series = {{Cancer Medicine}}, title = {{Alternative promoters and splicing create multiple functionally distinct isoforms of oestrogen receptor alpha in breast cancer and healthy tissues}}, url = {{http://dx.doi.org/10.1002/cam4.6508}}, doi = {{10.1002/cam4.6508}}, volume = {{12}}, year = {{2023}}, }