ESR1 fusions in breast cancer: functions, mechanisms and therapeutic opportunities

Approximately 70% of all breast cancers are driven by estrogen receptor-alpha (ERα) that binds the predominant circulating female estrogen, 17ꞵ-estradiol (E2). Because of this, drugs collectively termed "endocrine therapy (ET)" that either suppress E2 level or inhibit the activity of ERα have been used as first-line therapy. While initially effective, resistance to ET drugs occurs with subsequent lethal metastasis. The most common genetic alterations are point mutations in the ESR1 gene within the last exon encoding the ligand-binding domain (LBD), resulting in constitutively active ERα proteins. Recently, new oral selective estrogen receptor degraders (SERDs) that effectively target these point mutants have been Food and Drug Administration (FDA)-approved. In addition to these point mutations, ESR1 can undergo chromosomal translocations that produce gene fusions. One type of these fusions allows the ESR1 gene promoter to drive expression of the partner gene as a "promoter switch". The other type of ESR1 translocation creates a chimeric ESR1 fusion protein that contains the N-terminus, DNA-binding domain (DBD), and hinge region of ERα, but has the LBD replaced by a partner protein. Many of these in-frame ESR1 fusions have constitutive activity and cannot be inhibited by any ET, as the LBD of ERα is missing. This latter group of ESR1 fusion proteins promotes ET-resistance and invasive properties in cell lines and metastasis in mouse xenograft experiments. This review largely focuses on the in-frame chimeric ESR1 fusion proteins, highlighting current knowledge gaps in their mechanism(s) of action and how tumors that express them might be therapeutically targeted.