title: Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: YCR and Liz Dawn Pathology and Translational Sciences Centre, Leeds Teaching Hospitals and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Shaaban
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Suchita
authors.initials: S
authors.lastname: Karthik
authors.forename: Yalda
authors.initials: Y
authors.lastname: Alizadeh
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hughes
authors.forename: Lynn
authors.initials: L
authors.lastname: Harkins
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: John F
authors.initials: JF
authors.lastname: Robertson
authors.forename: Emma C
authors.initials: EC
authors.lastname: Paish
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Groome
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
mesh_terms: D019313:BRCA1 Protein / Q000096:biosynthesis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D018572:Disease-Free Survival; D047629:Estrogen Receptor beta / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D020033:Protein Isoforms / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D046888:Tissue Array Analysis
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D047629:Estrogen Receptor beta; D020033:Protein Isoforms; D011944:Receptors, Androgen; D011980:Receptors, Progesterone