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

Abstract

Estrogens play a pivotal role in the development and progression of prostate cancer (PCa). Their actions are mediated by estrogen receptors (ERs), particularly ERβ in the prostate epithelium. With the discovery of ERβ isoforms, data from previous studies that focused principally on the wild-type ERβ (ERβ1) may not be adequate in explaining the still controversial role of ERβ(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 ERβ1, ERβ2, and ERβ5 in PCa. ERβ2 was commonly found in the cytoplasm and was the most abundant isoform followed by ERβ1 localized predominantly in the nucleus, and ERβ5 was primarily located in the cytoplasm. Logistic regression analyses demonstrated that nuclear ERβ2 (nERβ2) is an independent prognostic marker for prostate specific antigen (PSA) failure and postoperative metastasis (POM). In a Kaplan–Meier analysis, the combined expression of both nERβ2 and cytoplasmic ERβ5 identified a group of patients with the shortest POM-free survival. Cox proportional hazard models revealed that nERβ2 predicted shorter time to POM. In concordance with IHC data, stable, ectopic expression of ERβ2 or ERβ5 enhanced PCa cell invasiveness but only PCa cells expressing ERβ5 exhibited augmented cell migration. This is the first study to uncover a metastasis-promoting role of ERβ2 and ERβ5 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.

Estrogen receptor β transcript variants associate with oncogene expression in endometrial cancer

“…Our study observing elevated ERβ5 mRNA levels in endometrial cancer, particularly in G3 tumors, is in line with the latter study and with reports from breast and prostate tissue (28,30,40). The demonstrated association of ERβ5 and 5 exonskipped isoforms with the oncogene and cell cycle promoter MYBL2 (B-MYB) suggests that these ERβ variants may be involved in tumor growth.…”

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

“…Construction of ER␤1 Stably Expressed Cell Lines-Stably expressed cell lines were constructed according to the published data (33). Full-length ER␤1 or LacZ (negative control) was subcloned, respectively, into pLenti6 lentiviral vector by Multisite Gateway Cloning (Invitrogen) and transfected into 293FT for production of lentivirus.…”

ERβ Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

“…In particular, it has been correlated with increased survival and invasiveness of prostate and ovarian cancer cells. In breast cancer, nuclear ERb2 has been associated negatively with metastasis and cytoplasmic ERb2 with worse outcome (49,50). ERb2 has been suggested to elicit its biologic functions by modulating the transcriptional activity of wild-type ERa and ERb through heterodimerization or by interacting with the membrane and cytoplasmic signaling cascade (6).…”