Figure 2.

Action of estrogen receptor β (ERβ) in breast cancer. Different ligands, such as estrogens, antiestrogens, and SERMs, activate non-genomic and genomic signaling of ERβ. In non-genomic signaling, ERβ interacts with membrane proteins (eg, G proteins, caveolin 1) and other interacting proteins (IPs) to activate kinase signaling pathways. In genomic signaling, liganded ERβ1 homodimerize or heterodimerize with ERβ isoforms or ERα and translocate from the cytoplasm to the nucleus. The homo- or heterodimer directly binds to estrogen response elements (EREs) or are tethered to other TFs (eg, AP1) in the promoter region or cis-regulatory sequences of target genes to facilitate gene transcription. Specific co-regulators (CoR) are believed to interact with ERβ to modulate gene transcription. ERβ may also translocate into mitochondria and interact with proteins involved in mitochrondrial ribosome synthesis and organization. ERβ has been found (or is expected to be) phosphorylated, ubiquitylated, or palmitoylated for gene transactivation, degradation, or membrane targeting, respectively. Expression of ERβ isoforms other than wild-type ERβ1 can be potential prognostic markers in breast cancer. For example, nuclear ERβ2 and ERβ5 were found to be associated with better patient survival; however, cytoplasmic ERβ2 was significantly correlated with worse outcome. Interactions of specific protein partners are believed to contribute to the functional roles of ERβ1 and its isoforms in breast cancer. Smiley and sad face represents good and bad prognosis in breast cancer, respectively.