Estrogen receptor β2 and β5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion

Estrogens play a pivotal role in the development and progression of prostate cancer (PCa). Their actions are mediated by estrogen receptors (ERs), particularly ER beta in the prostate epithelium. With the discovery of ER beta isoforms, data from previous studies that focused principally on the wild-type ER beta (ER beta 1) may not be adequate in explaining the still controversial role of ER beta(s) in prostate carcinogenesis. In this study, using newly generated isoform-specific antibodies, immunohistochemistry (IHC) was performed on a tumor microarray comprised of 144 specimens. IHC results were correlated with pathological and clinical follow-up data to delineate the distinct roles of ER beta 1, ER beta 2, and ER beta 5 in PCa. ER beta 2 was commonly found in the cytoplasm and was the most abundant isoform followed by ER beta 1 localized predominantly in the nucleus, and ER beta 5 was primarily located in the cytoplasm. Logistic regression analyses demonstrated that nuclear ER beta 2 (nER beta 2) is an independent prognostic marker for prostate specific antigen (PSA) failure and post operative metastasis (POM). In a Kaplan-Meier analysis, the combined expression of both nER beta 2 and cytoplasmic ER beta 5 identified a group of patients with the shortest POM-free survival. Cox proportional hazard models revealed that nER beta 2 predicted shorter time to POM. In concordance with IHC data, stable, ectopic expression of ER beta 2 or ER beta 5 enhanced PCa cell invasiveness but only PCa cells expressing ER beta 5 exhibited augmented cell migration. This is the first study to uncover a metastasis-promoting role of ER beta 2 and ER beta 5 in PCa, and show that the two isoforms, singularly and conjointly, have prognostic values for PCa progression. These findings may aid future clinical management of PCa. Endocrine-Related Cancer (2010) 17 675-689