ERβ Isoforms Have Differential Clinical Significance in Breast Cancer Subtypes and Subgroups

Simple Summary ER beta, an ER subtype first identified in 1996, is significantly expressed in ER alpha-negative breast cancer (BCa) and TNBC. Many studies investigated mostly ER beta 1 protein expression in the entire cohort of BCa, and the results are inconsistent. In this study, we simultaneously investigated both ER beta mRNA and three ER beta 1, 2, and 5 protein isoforms in various subtypes and subgroups of BCa. Each ER beta isoform's mRNA and protein expression seemingly plays a significant role in BCa subtypes and subgroups, and ER beta 2 mRNA expression is risk factor for poor outcome. Studies in a large cohort of BCa are needed to explore the potential usefulness of ER beta as a prognostic and predictive marker and a therapeutic target in BCa. Furthermore, the standardization of a ER beta testing protocol may be required for ER beta testing to be utilized in a clinical setting. ER beta, an ER subtype first identified in 1996, is highly expressed in different types of BCa including ER alpha-negative BCa and TNBC. Many studies on ER beta expression investigated mostly on ER beta 1 protein expression in ER alpha-positive and ER alpha-negative BCa combined. The results are conflicting. This may be due to the complexity of ER beta isoforms, subject heterogeneity, and various study designs targeting different ER beta isoforms and either ER beta protein or mRNA expression, as well as to the lack of a standardized testing protocol. Herein, we simultaneously investigated both mRNA and protein expression of ER beta isoforms 1, 2, and 5 in different BCa subtypes and clinical characteristics. Patient samples (138) and breast cancer cell lines (BCC) reflecting different types of BCa were tested for ER alpha and ER beta mRNA expression using quantitative real-time PCR, as well as for protein expression of ER alpha, ER beta 1, ER beta 2, and ER beta 5 isoforms, PR, HER2/neu, Ki-67, CK 5/6, and p53 using immunohistochemistry. Associations of ER beta isoform expression with clinical characteristics and overall survival (OS) were analyzed. ER beta 1, 2, and 5 isoforms are differentially expressed in different BCa subtypes including ER alpha-negative and TNBC. Each ER beta isoform seemingly plays a distinct role and is associated with clinical tumor characteristics and patient outcomes. ER beta isoform expression is significantly associated with >15% Ki-67 positivity and poor prognostic markers, and it predicts poorer OS, mostly in the subgroups. High ER beta 2 and 5 isoform expression in ER alpha-negative BCa and TNBC is predictive of poor OS. Further investigation of ER beta isoforms in a larger cohort of BCa subgroups is needed to evaluate the role of ER beta for the potential usefulness of ER beta as a prognostic and predictive marker and for therapeutic use. The inconsistent outcomes of ER beta isoform mRNA or protein expression in many studies suggest that the standardization of ER beta testing would facilitate the use of ER beta in a clinical setting.

Automated summary

In this study, the mRNA and protein expression of different isoforms of ER beta in various subtypes of breast cancer were simultaneously investigated. Each isoform of ER beta seems to play a significant role in different subtypes of breast cancer, and the expression of ER beta 2 mRNA is associated with poor prognosis. Further research in a larger cohort is needed to explore the potential usefulness of ER beta as a prognostic and predictive marker, as well as a therapeutic target in breast cancer. Standardization of ER beta testing may also be necessary for its clinical utilization.