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 journalArticlepeer-review

201 Citations (Scopus)


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
Issue number16
Publication statusPublished - 15 Aug 2008
Externally publishedYes


  • 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


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