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Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients

Authors' Affiliations: ¹ YCR and Liz Dawn Pathology and Translational Sciences Centre, Leeds Teaching Hospitals and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom; ² Department of Histopathology and ³ Professorial Unit of Surgery, Nottingham University Hospitals Trust and University of Nottingham, Nottingham, United Kingdom; ⁴ Medical Research Council Human Reproductive Sciences Unit, Queen's Medical Research Institute, Edinburgh, United Kingdom; and ⁵ Oxford Brookes University, Oxford, United Kingdom

Requests for reprints: Valerie Speirs, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds LS9 7TF, United Kingdom. Phone: 44-113-3438633; Fax: 44-113-3438431; E-mail: v.speirs{at}leeds.ac.uk.

Purpose: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-β in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERβ1, ERβ2, and ERβ5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up.

Experimental Design: Tissue microarrays were stained with ERβ1, ERβ2, and ERβ5 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 ERβ2 and ERβ5, but not ERβ1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERβ2 additionally with DFS (P = 0.013). ERβ2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ER, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERβ2 and ER had better OS and DFS. Cytoplasmic ERβ2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERβ2 expression had significantly worse outcome (P = 0.0014).

Conclusions: This is the first study elucidating the prognostic role of ERβ1, ERβ2, and ERβ5 in a large breast cancer series. ERβ2 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 ER.