Reprogramming of amino acid transporters to support aspartate and glutamate dependency sustains endocrine resistance in breast cancer
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Authors
Bacci, MLorito, N
Ippolito, L
Ramazzotti, M
Luti, S
Romagnoli, S
Parri, M
Bianchini, F
Cappellesso, F
Virga, F
Gao, Q
Simoes, Bruno M
Marangoni, E
Martin, LA
Comito, G
Ferracin, M
Giannoni, E
Mazzone, M
Chiarugi, P
Morandi, A
Affiliation
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, ItalyIssue Date
2019
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Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER(+)) breast cancers. Despite its efficacy, approximately 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.Citation
Bacci M, Lorito N, Ippolito L, Ramazzotti M, Luti S, Romagnoli S, et al. Reprogramming of amino acid transporters to support aspartate and glutamate dependency sustains endocrine resistance in breast cancer. Cell Rep. 2019 Jul 2;28(1):104-18 e8.Journal
Cell ReportsDOI
10.1016/j.celrep.2019.06.010PubMed ID
31269432Additional Links
https://dx.doi.org/10.1016/j.celrep.2019.06.010Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2019.06.010
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