ESR1 fusions and therapeutic resistance in metastatic breast cancer

Abstract

Breast cancer is the most frequent female malignant tumor, and the leading cause of cancer death in women worldwide. The most common subtype of breast cancer is hormone receptor positive that expresses the estrogen receptor (ER). Targeting ER with endocrine therapy (ET) is the current standard of care for ER positive (ER+) breast cancer, reducing mortality by up to 40% in early- stage disease. However, resistance to ET represents a major clinical challenge for ER+ breast cancer patients leading to disease recurrence or progression of metastatic disease. Salient drivers of ET resistance are missense mutations in the ER gene (ESR1) leading to constitutive transcriptional activity and reduced ET sensitivity. These mutations are particularly prominent and deleterious in metastatic breast cancer (MBC). In addition to activating ESR1 point mutations, emerging evidence imposes that chromosomal translocation involving the ESR1 gene can also drive ET resistance through the formation of chimeric transcription factors with constitutive transcriptional activity. Although these ESR1 gene fusions are relatively rare, they are enriched in ET resistant metastatic disease. This review discusses the characteristics of ER fusion proteins and their association with clinical outcomes in more aggressive and metastatic breast cancer. The structure and classification of ER fusion proteins based on function and clinical significance are also addressed. Finally, this review summarizes the metastatic phenotypes exhibited by the ER fusion proteins and their role in intrinsic ET resistance.

Keywords: ESR1 fusion; SERD; breast cancer; endocrine therapy resistance; estrogen receptor.

Figure 1

Schematic structure of ESR1-e2>CCDC170 and ESR1-e6>fusion proteins. Non-coding exons (e) 1 and 2 are shown as white boxes, while encoding domains in the ESR1 codon structure are presented in gray. ER is comprised of four domains: N-terminal activation function-1 (AF-1), DNA binding domain (DBD), hinge region and C-terminal ligand binding domain (AF-2/LBD). ESR1-e2>CCDC170 fusion proteins retain the first two non-coding exons of ESR1 (ESR1-e2) and link to the coiled-coil domain containing 170 (CCDC170) gene generating truncated CCDC170 proteins (ΔCCDC170). ESR1-e6>fusions preserve the first 6 exons of ESR1 (ESR1-e6), while replace the LBD by a 3’ fusion partner.