Gene signatures and potential therapeutic targets of amino acid metabolism in estrogen receptor-positive breast cancer.(2/2)

lthough adjuvant tamoxifen therapy for estrogen receptor (ER) positive (ER+) breast cancer cases can be beneficial to patients, a significant number of patients develop metastasis or undergo recurrence. Therefore, identifying potential diagnostic and prognostic biomarkers for these patients is urgently needed. High-throughput technology used holistic approach to observe differences among a thousand profiles of gene expression, which provide a comprehensive level to investigate functional genomics and biological process extensively. Since predictive markers and therapeutic strategies for tamoxifen-resistant ER+ breast cancer are not clear, and miRNAs are one of the focal research point in cancer studies of owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematical investigation is required for understanding the modulation of gene expression in tamoxifen-resistant patients. Through a bioinformatics analysis and a venn diagram, we revealed that 5 miRNAs, hsa-miR-532-5p, hsa-miR-1180, hsa-miR-152, hsa-miR-578, and hsa-miR-128 may play an essential role for recurrence in tamoxifen-treated patients. Analysis of pathway database demonstrated that Glutamine Synthetase (GLUL) was involved in cell cycle and immune response
Interleukin-4 (IL-4)-induced regulators of cell growth survival, differentiation and metabolism related pathway.The experimental data also confirmed that knockdown of GLUL in breast cancer cell line decreased cell proliferation, and influenced expressions of downstream molecules, including IL-4 and cell cycle related genes. Through a connectivity map (CMap) analysis, we revealed that certain drugs/molecules with highly negative correlations serve as a potential treatment for tamoxifen-resistant breast cancer patients, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL, which provide new targets for treatment of tamoxifenresistant reast cancer patients.