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    Reprogramming of amino acid transporters to support aspartate and glutamate dependency sustains endocrine resistance in breast cancer

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    Authors
    Bacci, M
    Lorito, 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
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    Affiliation
    Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    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 Reports
    URI
    http://hdl.handle.net/10541/621996
    DOI
    10.1016/j.celrep.2019.06.010
    PubMed ID
    31269432
    Additional Links
    https://dx.doi.org/10.1016/j.celrep.2019.06.010
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.celrep.2019.06.010
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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