Estrogen Receptor beta Expression and Its Clinical Implication in Breast Cancers: Favorable or Unfavorable?

There are two estrogen receptor (ER) genes (ESR1/ER alpha and ESR2/ER beta) in humans. Of those. ER beta, the second ER isotype identified in 1996, is differentially expressed in different phenotypes and molecular subtypes of breast cancer (BCa), and is highly expressed in ER alpha-negative BCa and triple-negative BCa (TNBC). This review summarizes the potential clinical relevance of ER beta in BCa and the challenges associated with studies on the role of ER beta in BCa. The experimental and clinical studies evaluating clinical outcomes and associations with clinical characteristics and responses to endocrine therapy on targeting ERP reviewed herein indicate that ER beta is a clinically important biomarker in BCa. The reviewed studies also suggest that each ER beta isoform has a distinct role in BCa subtypes and the potential of novel- targeted therapies in BCa, especially ER alpha-negative BCa and TNBC. However, the findings of many studies on ER beta are inconsistent, and the exact role of ER beta in BCa remains elusive; this may potentially be attributed to the complexity of ER beta isoforms, but also to the lack of standardized testing protocol. Thus, successful clinical application of ER beta requires the development of standardized, reproducible, and objective measurement methods for ER beta that can be widely and routinely applied in clinical setting.