Transcriptional Reprogramming Differentiates Active from Inactive ESR1 Fusions in Endocrine Therapy-Refractory...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Estrogen receptor alpha-positive (ERα+) metastatic breast cancer (MBC) often develops resistance to endocrine therapy.
• Genomic analysis has revealed ESR1 gene translocations creating chimeric proteins that can activate the estrogen receptor (ER) pathway without estrogen.

Purpose of the Study:

• To functionally characterize novel ESR1 gene fusions and identify a diagnostic gene signature for these alterations in ERα+ MBC.
• To assess the utility of this signature in patient-derived xenografts and clinical MBC samples.

Main Methods:

• Functional screening of 15 ESR1 fusions for their impact on cancer cell behavior.
• RNA sequencing to identify gene expression patterns associated with active ESR1 fusions.
• Development and validation of a 24-gene signature in xenografts and MBC patient samples.

Main Results:

• Ten of 15 screened ESR1 fusions promoted estradiol-independent cell growth, invasion, and resistance to fulvestrant.
• A specific gene expression pattern was identified for functional ESR1 fusions, which was condensed into a 24-gene signature.
• The 24-gene signature accurately identified ESR1 gene fusions and activating ESR1 LBD point mutations in patient samples.

Conclusions:

• A 24-gene signature effectively detects diverse somatic ESR1 mutations, including translocations and point mutations, driving endocrine treatment failure in MBC.
• This signature offers an efficient approach for screening MBC patients and guiding precision medicine strategies for those with ESR1 alterations.