Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients

Abeer M Shaaban, Andrew R Green, Suchita Karthik, Yalda Alizadeh, Thomas A Hughes, Lynn Harkins, Ian O Ellis, John F Robertson, Emma C Paish, Philippa T K Saunders, Nigel P Groome, Valerie Speirs

Research output: Contribution to journalArticle

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Abstract

PURPOSE: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-beta in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERbeta1, ERbeta2, and ERbeta5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up.

EXPERIMENTAL DESIGN: Tissue microarrays were stained with ERbeta1, ERbeta2, and ERbeta5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS).

RESULTS: Nuclear ERbeta2 and ERbeta5, but not ERbeta1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERbeta2 additionally with DFS (P = 0.013). ERbeta2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERalpha, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERbeta2 and ERalpha had better OS and DFS. Cytoplasmic ERbeta2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERbeta2 expression had significantly worse outcome (P = 0.0014).

CONCLUSIONS: This is the first study elucidating the prognostic role of ERbeta1, ERbeta2, and ERbeta5 in a large breast cancer series. ERbeta2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERalpha.

Original languageEnglish
Pages (from-to)5228-35
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number16
DOIs
Publication statusPublished - 15 Aug 2008

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Estrogen Receptor alpha
Breast Neoplasms
Disease-Free Survival
Survival
Staining and Labeling
Estrogen Receptor beta
Androgen Receptors
Progesterone Receptors
Blood Vessels
Neoplasms
Protein Isoforms
Immunohistochemistry
Neoplasm Metastasis
Antibodies
Therapeutics

Keywords

  • BRCA1 Protein
  • Blotting, Western
  • Breast Neoplasms
  • Cell Nucleus
  • Cytoplasm
  • Disease-Free Survival
  • Estrogen Receptor beta
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Prognosis
  • Protein Isoforms
  • Receptors, Androgen
  • Receptors, Progesterone
  • Tissue Array Analysis
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. / Shaaban, Abeer M; Green, Andrew R; Karthik, Suchita; Alizadeh, Yalda; Hughes, Thomas A; Harkins, Lynn; Ellis, Ian O; Robertson, John F; Paish, Emma C; Saunders, Philippa T K; Groome, Nigel P; Speirs, Valerie.

In: Clinical Cancer Research, Vol. 14, No. 16, 15.08.2008, p. 5228-35.

Research output: Contribution to journalArticle

Shaaban, AM, Green, AR, Karthik, S, Alizadeh, Y, Hughes, TA, Harkins, L, Ellis, IO, Robertson, JF, Paish, EC, Saunders, PTK, Groome, NP & Speirs, V 2008, 'Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients', Clinical Cancer Research, vol. 14, no. 16, pp. 5228-35. https://doi.org/10.1158/1078-0432.CCR-07-4528
Shaaban, Abeer M ; Green, Andrew R ; Karthik, Suchita ; Alizadeh, Yalda ; Hughes, Thomas A ; Harkins, Lynn ; Ellis, Ian O ; Robertson, John F ; Paish, Emma C ; Saunders, Philippa T K ; Groome, Nigel P ; Speirs, Valerie. / Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 16. pp. 5228-35.
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abstract = "PURPOSE: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-beta in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERbeta1, ERbeta2, and ERbeta5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up.EXPERIMENTAL DESIGN: Tissue microarrays were stained with ERbeta1, ERbeta2, and ERbeta5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS).RESULTS: Nuclear ERbeta2 and ERbeta5, but not ERbeta1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERbeta2 additionally with DFS (P = 0.013). ERbeta2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERalpha, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERbeta2 and ERalpha had better OS and DFS. Cytoplasmic ERbeta2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERbeta2 expression had significantly worse outcome (P = 0.0014).CONCLUSIONS: This is the first study elucidating the prognostic role of ERbeta1, ERbeta2, and ERbeta5 in a large breast cancer series. ERbeta2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERalpha.",
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TY - JOUR

T1 - Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients

AU - Shaaban, Abeer M

AU - Green, Andrew R

AU - Karthik, Suchita

AU - Alizadeh, Yalda

AU - Hughes, Thomas A

AU - Harkins, Lynn

AU - Ellis, Ian O

AU - Robertson, John F

AU - Paish, Emma C

AU - Saunders, Philippa T K

AU - Groome, Nigel P

AU - Speirs, Valerie

PY - 2008/8/15

Y1 - 2008/8/15

N2 - PURPOSE: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-beta in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERbeta1, ERbeta2, and ERbeta5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up.EXPERIMENTAL DESIGN: Tissue microarrays were stained with ERbeta1, ERbeta2, and ERbeta5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS).RESULTS: Nuclear ERbeta2 and ERbeta5, but not ERbeta1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERbeta2 additionally with DFS (P = 0.013). ERbeta2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERalpha, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERbeta2 and ERalpha had better OS and DFS. Cytoplasmic ERbeta2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERbeta2 expression had significantly worse outcome (P = 0.0014).CONCLUSIONS: This is the first study elucidating the prognostic role of ERbeta1, ERbeta2, and ERbeta5 in a large breast cancer series. ERbeta2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERalpha.

AB - PURPOSE: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-beta in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERbeta1, ERbeta2, and ERbeta5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up.EXPERIMENTAL DESIGN: Tissue microarrays were stained with ERbeta1, ERbeta2, and ERbeta5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS).RESULTS: Nuclear ERbeta2 and ERbeta5, but not ERbeta1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERbeta2 additionally with DFS (P = 0.013). ERbeta2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERalpha, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERbeta2 and ERalpha had better OS and DFS. Cytoplasmic ERbeta2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERbeta2 expression had significantly worse outcome (P = 0.0014).CONCLUSIONS: This is the first study elucidating the prognostic role of ERbeta1, ERbeta2, and ERbeta5 in a large breast cancer series. ERbeta2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERalpha.

KW - BRCA1 Protein

KW - Blotting, Western

KW - Breast Neoplasms

KW - Cell Nucleus

KW - Cytoplasm

KW - Disease-Free Survival

KW - Estrogen Receptor beta

KW - Female

KW - Humans

KW - Immunohistochemistry

KW - Kaplan-Meier Estimate

KW - Prognosis

KW - Protein Isoforms

KW - Receptors, Androgen

KW - Receptors, Progesterone

KW - Tissue Array Analysis

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/1078-0432.CCR-07-4528

DO - 10.1158/1078-0432.CCR-07-4528

M3 - Article

C2 - 18698041

VL - 14

SP - 5228

EP - 5235

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 16

ER -