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

TitleTranscriptional Reprogramming Differentiates Active from Inactive ESR1 Fusions in Endocrine Therapy-Refractory Metastatic Breast Cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsGou, X, Anurag, M, Lei, JT, Kim, B-J, Singh, P, Seker, S, Fandino, D, Han, A, Rehman, S, Hu, J, Korchina, V, Doddapaneni, H, Dobrolecki, LE, Mitsiades, N, Lewis, MT, Welm, AL, Li, S, Lee, AV, Robinson, DR, Foulds, CE, Ellis, MJ
JournalCancer Res
Date Published2021 Dec 15
KeywordsAnimals, Antineoplastic Agents, Hormonal, Apoptosis, Biomarkers, Tumor, Breast Neoplasms, Cell Proliferation, Drug Resistance, Neoplasm, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Mutation, Oncogene Proteins, Fusion, Prognosis, Survival Rate, Transcriptome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays

Genomic analysis has recently identified multiple gene translocations in estrogen receptor alpha-positive (ERα) metastatic breast cancer (MBC) that encode chimeric proteins whereby the ESR1 ligand binding domain (LBD) is replaced by C-terminal sequences from many different gene partners. Here we functionally screened 15 ESR1 fusions and identified 10 that promoted estradiol-independent cell growth, motility, invasion, epithelial-to-mesenchymal transition, and resistance to fulvestrant. RNA sequencing identified a gene expression pattern specific to functionally active ESR1 gene fusions that was subsequently reduced to a diagnostic 24-gene signature. This signature was further examined in 20 ERα patient-derived xenografts and in 55 ERα MBC samples. The 24-gene signature successfully identified cases harboring gene fusions and also accurately diagnosed the presence of activating LBD point mutations. Therefore, the 24-gene signature represents an efficient approach to screening samples for the presence of diverse somatic mutations and translocations that drive endocrine treatment failure in MBC. SIGNIFICANCE: This study identifies a gene signature diagnostic for functional ESR1 fusions that drive poor outcome in advanced breast cancer, which could also help guide precision medicine approaches in patients harboring mutations.

Alternate JournalCancer Res
PubMed ID34711608
PubMed Central IDPMC9234971
Grant ListU54 CA224076 / CA / NCI NIH HHS / United States
U54 CA233223 / CA / NCI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
S10 OD023469 / OD / NIH HHS / United States
T32 CA203690 / CA / NCI NIH HHS / United States
T32 GM088129 / GM / NIGMS NIH HHS / United States
P50 CA186784 / CA / NCI NIH HHS / United States

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