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

Abstract

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

Keywords: Estrogen Receptor Beta; Patient Outcome Assessment; Prognosis; Survival Analysis; Therapeutic Uses.

Figure 1. Immunohistochemistry stains of ERα and ERβ protein expression in normal and benign breast tissue. ERα is expressed only in epithelial cells (A and C). ERβ expression (B and D) is expressed in benign epithelial cells and myoepithelial cells, stromal cells, and lymphocytes, and ERβ reaction is abundant and stronger than that of ERα (immunohistochemistry stain using polyclonal ERβ1 (385p/AR385-10R) antibody, original magnification ×20).

ER = estrogen receptor.

Figure 2. Hematoxylin and eosin stains of infiltrating duct carcinoma of BCa tissues (A) and immunohistochemistry stains of ERα (B) shows positive reaction only in neoplastic epithelial cells, whereas ERβ expression (C) shows strong and diffuse immunoreaction of neoplastic epithelial cells and stromal cells (original magnification ×20), (D) diffuse and intense staining of ERβ expression in nuclei (original magnification ×40), differential expression of ERβ in BCa types, (E) infiltrating lobular carcinoma, (F) apocrine carcinoma, (G) micropapillary carcinoma, (H) mucinous carcinoma (original magnification ×20).

BCa = breast cancer; ER = estrogen receptor.

Figure 3. Negative ERα staining in ERα-negative BCa (A), high expression of ERβ (B), co-expression of Her-2/neu (C) and P53 (D) of the same ERα- negative BCa cells (original magnification ×20).

ER = estrogen receptor; BCa = breast cancer.