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Cytoplasmic Estrogen Receptor in Breast Cancer

Welsh, Allison W. ; Lannin, Donald R. ; Young, Gregory S. ; Sherman, Mark E. ; Figueroa, Jonine D. ; Henry, N. Lynn ; Rydén, Lisa LU orcid ; Kim, Chungyeul ; Love, Richard R. and Schiff, Rachel , et al. (2012) In Clinical Cancer Research 18(1). p.118-126
Abstract
Purpose: In addition to genomic signaling, it is accepted that estrogen receptor-alpha (ER alpha) has nonnuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of nonnuclear ER in clinical specimens. Experimental Design: A panel of ER alpha-specific antibodies (SP1, MC20, F10, 60c, and 1D5) was validated by Western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, and 128)... (More)
Purpose: In addition to genomic signaling, it is accepted that estrogen receptor-alpha (ER alpha) has nonnuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of nonnuclear ER in clinical specimens. Experimental Design: A panel of ER alpha-specific antibodies (SP1, MC20, F10, 60c, and 1D5) was validated by Western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, and 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world. Results: Four of the antibodies specifically recognized ER by Western and QIF analysis, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with Pearson correlations (r(2) values) ranging from 0.87 to 0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other four antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%. Conclusions: Our data show ER alpha is present in the cytoplasm in a number of cases using multiple antibodies while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value. Clin Cancer Res; 18(1); 118-26. (C) 2011 AACR. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
18
issue
1
pages
118 - 126
publisher
American Association for Cancer Research Inc.
external identifiers
  • wos:000298758900014
  • scopus:84855432191
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-11-1236
language
English
LU publication?
yes
id
af5069bc-591c-4e11-bcf6-8f62877514db (old id 2358474)
date added to LUP
2016-04-01 10:28:30
date last changed
2025-04-04 14:33:18
@article{af5069bc-591c-4e11-bcf6-8f62877514db,
  abstract     = {{Purpose: In addition to genomic signaling, it is accepted that estrogen receptor-alpha (ER alpha) has nonnuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of nonnuclear ER in clinical specimens. Experimental Design: A panel of ER alpha-specific antibodies (SP1, MC20, F10, 60c, and 1D5) was validated by Western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, and 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world. Results: Four of the antibodies specifically recognized ER by Western and QIF analysis, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with Pearson correlations (r(2) values) ranging from 0.87 to 0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other four antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%. Conclusions: Our data show ER alpha is present in the cytoplasm in a number of cases using multiple antibodies while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value. Clin Cancer Res; 18(1); 118-26. (C) 2011 AACR.}},
  author       = {{Welsh, Allison W. and Lannin, Donald R. and Young, Gregory S. and Sherman, Mark E. and Figueroa, Jonine D. and Henry, N. Lynn and Rydén, Lisa and Kim, Chungyeul and Love, Richard R. and Schiff, Rachel and Rimm, David L.}},
  issn         = {{1078-0432}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{118--126}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Clinical Cancer Research}},
  title        = {{Cytoplasmic Estrogen Receptor in Breast Cancer}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-11-1236}},
  doi          = {{10.1158/1078-0432.CCR-11-1236}},
  volume       = {{18}},
  year         = {{2012}},
}