Estrogen receptor 1-Parkin RBR E3 ubiquitin protein ligase fusion protein (ESR1-PRKN)

The Estrogen receptor 1-Parkin RBR E3 ubiquitin protein ligase (ESR1-PRKN) fusion protein is a chimeric molecule resulting from a genomic rearrangement between the ESR1 and PRKN (formerly PARK2) genes, most frequently detected in patients with metastatic, estrogen receptor-positive (ER+) breast cancer (Hartmaier et al., 2018, Cancer Research). This fusion typically involves the N-terminal portion of the estrogen receptor, including its DNA-binding domain, fused to the C-terminal portion of the Parkin protein, often resulting in the loss of the ESR1 ligand-binding domain (Lei et al., 2018, Nature Communications). The loss of this domain leads to constitutive, ligand-independent transcriptional activity, which drives tumor growth even in the absence of estrogen or in the presence of aromatase inhibitors. Consequently, ESR1-PRKN fusions are a major mechanism of acquired endocrine resistance in breast cancer (Schiavon et al., 2015, Science Translational Medicine). While traditional therapies like tamoxifen may be ineffective, novel selective estrogen receptor degraders (SERDs) and other targeted agents are being investigated to overcome the signaling advantages provided by this fusion protein.

Other names

ESR1-PARK2 fusionEstrogen receptor alpha-Parkin fusionESR1-PRKN

Selective estrogen receptor degradation (SERD) and antagonism of the estrogen receptor alpha component to inhibit constitutive transcriptional activity (Lei et al., 2018, Nature Communications).