Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer
Marina Bacci,
Nicla Lorito,
Luigi Ippolito,
Matteo Ramazzotti,
Simone Luti,
Simone Romagnoli,
Matteo Parri,
Francesca Bianchini,
Federica Cappellesso,
Federico Virga,
Qiong Gao,
Bruno M. Simões,
Elisabetta Marangoni,
Lesley-Ann Martin,
Giuseppina Comito,
Manuela Ferracin,
Elisa Giannoni,
Massimiliano Mazzone,
Paola Chiarugi,
Andrea Morandi
Affiliations
Marina Bacci
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Nicla Lorito
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Luigi Ippolito
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Matteo Ramazzotti
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Simone Luti
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Simone Romagnoli
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Matteo Parri
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Francesca Bianchini
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Federica Cappellesso
VIB Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven 3000, Belgium
Federico Virga
VIB Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10126, Italy
Qiong Gao
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
Bruno M. Simões
Breast Cancer Now Research Unit, Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK
Elisabetta Marangoni
Institut Curie, PSL Research University, Translational Research Department, Paris 75248, France
Lesley-Ann Martin
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
Giuseppina Comito
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Manuela Ferracin
Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna 40126, Italy
Elisa Giannoni
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Massimiliano Mazzone
VIB Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven 3000, Belgium
Paola Chiarugi
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Andrea Morandi
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy; Corresponding author
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. : 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. Keywords: endocrine therapy, resistance, metabolic reprogramming, estrogen receptor, amino acid transporters, aspartate, glutamate, miRNA, SLCs
