ERβ in breast cancer—Onlooker, passive player, or active protector?

Abstract

The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

Lapatinib induces p27Kip1-dependent G₁ arrest through both transcriptional and post-translational mechanisms

“…42,43 We asked whether this is also the case in our system, and investigated whether this affects cellular response to lapatinib. To this end, we transiently transfected SK-BR-3 cells with ERβ1-or ERβ2-expressing vectors, and treated them with 0.1 μM lapatinib for 48 h. We found that ERβ1 expression inhibited cell proliferation and enhanced G 1 cell cycle arrest, both in the presence and absence of lapatinib ( Fig.…”

A bi-faceted role of estrogen receptor β in breast cancer

“…In particular, one critical discovery has been the identification of a second estrogen receptor (ER), called ERb (Kuiper et al 1996), in contrast to the classical ERa, which can also mediate estrogen action in target cells. The discovery of ERb has led to a full reevaluation of estrogen action in all target tissues, including human breast cancer (Fox et al 2008). However, despite over 15 years of research, the exact role, if any, played by ERb in human breast cancer remains elusive (Fox et al 2008, Thomas & Gustafsson 2011, Murphy & Leygue 2012.…”

Genistein inhibits placental choriocarcinoma cell line JAR invasion through ERβ/MTA3/Snail/E-cadherin pathway

“…Both monomeric forms of each receptor subtype are approximately 60 kDa and both subtypes bind estradiol-17 with high affinity but differ in DNA-binding affinity. These two ER subtypes are capable of mediating different functions depending on the nature of bound ligands, post-translational modifications, cofactor interactions and promoter response elements (2,3). The expression and functions of the two ER subtypes in placenta were previously confirmed.…”