Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer.
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Embargo End Date
ICR Authors
Authors
Bacci, M
Lorito, N
Ippolito, L
Ramazzotti, M
Luti, S
Romagnoli, S
Parri, M
Bianchini, F
Cappellesso, F
Virga, F
Gao, Q
Simões, BM
Marangoni, E
Martin, L-A
Comito, G
Ferracin, M
Giannoni, E
Mazzone, M
Chiarugi, P
Morandi, A
Lorito, N
Ippolito, L
Ramazzotti, M
Luti, S
Romagnoli, S
Parri, M
Bianchini, F
Cappellesso, F
Virga, F
Gao, Q
Simões, BM
Marangoni, E
Martin, L-A
Comito, G
Ferracin, M
Giannoni, E
Mazzone, M
Chiarugi, P
Morandi, A
Document Type
Journal Article
Date
2019-07-02
Date Accepted
2019-06-03
Abstract
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.
Citation
Cell reports, 2019, 28 (1), pp. 104 - 118.e8
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247