EPRS is a critical regulator of cell proliferation and estrogen signaling in ER + breast cancer

// Igor Katsyv 1, 2, 3 , Minghui Wang 2, 3 , Won Min Song 2, 3 , Xianxiao Zhou 2, 3 , Yongzhong Zhao 2, 3 , Sun Park 4 , Jun Zhu 2, 3 , Bin Zhang 2, 3, 5 , Hanna Y. Irie 4, 5 1 Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 2 Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 3 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 4 Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 5 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Correspondence to: Bin Zhang, email: bin.zhang@mssm.edu Hanna Y. Irie, email: hanna.irie@mssm.edu Keywords: breast cancer, ER+, EPRS, gene networks Received: May 04, 2016      Accepted: August 25, 2016      Published: September 06, 2016 ABSTRACT Aminoacyl tRNA synthetases (ARSs) are a class of enzymes with well-conserved housekeeping functions in cellular translation. Recent evidence suggests that ARS genes may participate in a wide array of cellular processes, and may contribute to the pathology of autoimmune disease, cancer, and other diseases. Several studies have suggested a role for the glutamyl prolyl tRNA synthetase ( EPRS ) in breast cancers, although none has identified any underlying mechanism about how EPRS contributes to carcinogenesis. In this study, we identified EPRS as upregulated in estrogen receptor positive (ER+) human breast tumors in the TCGA and METABRIC cohorts, with copy number gains in nearly 50% of samples in both datasets. EPRS expression is associated with reduced overall survival in patients with ER+ tumors in TCGA and METABRIC datasets. EPRS expression was also associated with reduced distant relapse-free survival in patients treated with adjuvant tamoxifen monotherapy for five years, and EPRS -correlated genes were highly enriched for genes predictive of a poor response to tamoxifen. We demonstrated the necessity of EPRS for proliferation of tamoxifen-resistant ER+ breast cancer, but not ER- breast cancer cells. Transcriptomic profiling showed that EPRS regulated cell cycle and estrogen response genes. Finally, we constructed a causal gene network based on over 2500 ER+ breast tumor samples to build up an EPRS -estrogen signaling pathway. EPRS and its regulated estrogenic gene network may offer a promising alternative approach to target ER+ breast cancers that are refractory to current anti-estrogens.