Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer
| Autor: | Bruno M Simões, Andrea Morandi, Giuseppina Comito, Marina Bacci, Simone Romagnoli, Elisabetta Marangoni, Paola Chiarugi, Massimiliano Mazzone, Matteo Ramazzotti, Nicla Lorito, Manuela Ferracin, Simone Luti, Lesley-Ann Martin, Francesca Bianchini, Qiong Gao, Federico Virga, Federica Cappellesso, Matteo Parri, Elisa Giannoni, Luigi Ippolito |
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| Přispěvatelé: | Bacci M., Lorito N., Ippolito L., Ramazzotti M., Luti S., Romagnoli S., Parri M., Bianchini F., Cappellesso F., Virga F., Gao Q., Simoes B.M., Marangoni E., Martin L.-A., Comito G., Ferracin M., Giannoni E., Mazzone M., Chiarugi P., Morandi A. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Amino Acid Transport Systems Neutral Drug Resistance Estrogen receptor SLCs THERAPY amino acid transporter Mice 0302 clinical medicine metabolic reprogramming Neoplasm Metastasis amino acid transporters aspartate endocrine therapy estrogen receptor glutamate miRNA resistance lcsh:QH301-705.5 Inbred BALB C chemistry.chemical_classification Heterologous Mice Inbred BALB C Tumor biology Manchester Cancer Research Centre Chemistry SIGNATURE Glutamate receptor SLC1A2 Prognosis 3. Good health Amino acid Amino Acid Transport Systems Neutral Animals Aspartic Acid Breast Neoplasms Cell Line Tumor Cell Survival Drug Resistance Neoplasm Estrogen Receptor alpha Excitatory Amino Acid Transporter 2 Female GATA2 Transcription Factor Gas Chromatography-Mass Spectrometry Gene Expression Regulation Neoplastic Glutamic Acid Humans MicroRNAs Transcriptome Transplantation Heterologous TARGET SURVIVAL AUTOPHAGY Life Sciences & Biomedicine EXPRESSION DATA General Biochemistry Genetics and Molecular Biology Article Cell Line 03 medical and health sciences Downregulation and upregulation Amino acid transporter TAMOXIFEN Neoplastic Transplantation Science & Technology RECEPTOR ResearchInstitutes_Networks_Beacons/mcrc Autophagy Transporter Cell Biology 030104 developmental biology Gene Expression Regulation lcsh:Biology (General) CELLS METASTASIS biology.protein Cancer research Neoplasm 030217 neurology & neurosurgery |
| Zdroj: | Bacci, M, Lorito, N, Ippolito, L, Ramazzotti, M, Luti, S, Romagnoli, S, Parri, M, Bianchini, F, Cappellesso, F, Virga, F, Gao, Q, M Simoes, B, Marangoni, E, Martin, L-A, Comito, G, Ferracin, M, Giannoni, E, Mazzone, M, Chiarugi, P & Morandi, A 2019, ' Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer ', Cell Reports, vol. 28, no. 1, pp. 104-118 . https://doi.org/10.1016/j.celrep.2019.06.010 Cell Reports Cell Reports, Vol 28, Iss 1, Pp 104-118.e8 (2019) |
| Popis: | Summary Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER+) breast cancers. Despite its efficacy, ∼40% of women relapse with ET-resistant (ETR) disease. A global transcription analysis in ETR cells reveals a downregulation of the neutral and basic amino acid transporter SLC6A14 governed by enhanced miR-23b-3p expression, resulting in impaired amino acid metabolism. This altered amino acid metabolism in ETR cells is supported by the activation of autophagy and the enhanced import of acidic amino acids (aspartate and glutamate) mediated by the SLC1A2 transporter. The clinical significance of these findings is validated by multiple orthogonal approaches in a large cohort of ET-treated patients, in patient-derived xenografts, and in in vivo experiments. Targeting these amino acid metabolic dependencies resensitizes ETR cells to therapy and impairs the aggressive features of ETR cells, offering predictive biomarkers and potential targetable pathways to be exploited to combat or delay ETR in ER+ breast cancers. Graphical Abstract Highlights • ETR cells show high miR-23b-3p that reduces SLC6A14 and amino acids upload • ETR cells promote autophagy and aspartate and glutamate import via SLC1A2 • Aspartate and glutamate fuel anabolic and catabolic pathways in ETR breast cancers • Targeting amino acid metabolic reprogramming is effective in ETR cells Bacci et al. find that endocrine-resistant ER+ breast cancers are characterized by enhanced miR-23b-3p, autophagy activation, and import of aspartate and glutamate that fuel catabolic and anabolic pathways, which are essential for their aggressive features. The molecular players involved in this metabolic scenario are of clinical significance and have prognostic and predictive value. |
| Databáze: | OpenAIRE |
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