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

Balcazar Lopez, Carlos Enrique LU ; Albrecht, Juliane LU orcid ; Hafstað, Völundur LU ; Börjesson Freitag, Cornelia LU ; Vallon-Christersson, Johan LU orcid ; Bellodi, Cristian LU and Persson, Helena LU orcid (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
; ; ; ; ; and
organization
publishing date
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}},
}