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

doi:10.1016/j.celrep.2019.06.010

Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer

Cell Rep. 2019 Jul 2;28(1):104-118.e8. doi: 10.1016/j.celrep.2019.06.010.

Authors

Marina Bacci¹, Nicla Lorito¹, Luigi Ippolito¹, Matteo Ramazzotti¹, Simone Luti¹, Simone Romagnoli¹, Matteo Parri¹, Francesca Bianchini¹, Federica Cappellesso², Federico Virga³, Qiong Gao⁴, Bruno M Simões⁵, Elisabetta Marangoni⁶, Lesley-Ann Martin⁴, Giuseppina Comito¹, Manuela Ferracin⁷, Elisa Giannoni¹, Massimiliano Mazzone², Paola Chiarugi¹, Andrea Morandi⁸

Affiliations

¹ Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy.
² VIB Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven 3000, Belgium.
³ 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.
⁴ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
⁵ Breast Cancer Now Research Unit, Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK.
⁶ Institut Curie, PSL Research University, Translational Research Department, Paris 75248, France.
⁷ Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna 40126, Italy.
⁸ Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy. Electronic address: andrea.morandi@unifi.it.

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.

Keywords: SLCs; amino acid transporters; aspartate; endocrine therapy; estrogen receptor; glutamate; metabolic reprogramming; miRNA; resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport Systems / genetics
Amino Acid Transport Systems / metabolism*
Amino Acid Transport Systems, Neutral / genetics
Animals
Aspartic Acid / metabolism*
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology*
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism
Excitatory Amino Acid Transporter 2 / genetics
Excitatory Amino Acid Transporter 2 / metabolism*
Female
GATA2 Transcription Factor / genetics
GATA2 Transcription Factor / metabolism
Gas Chromatography-Mass Spectrometry
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / genetics
Glutamic Acid / metabolism*
Humans
Mice
Mice, Inbred BALB C
MicroRNAs / genetics
MicroRNAs / metabolism
Neoplasm Metastasis
Prognosis
Transcriptome / genetics
Transplantation, Heterologous

Substances

Amino Acid Transport Systems
Amino Acid Transport Systems, Neutral
Estrogen Receptor alpha
Excitatory Amino Acid Transporter 2
GATA2 Transcription Factor
GATA2 protein, human
MIRN23b microRNA, human
MicroRNAs
SLC1A2 protein, human
SLC6A14 protein, human
Aspartic Acid
Glutamic Acid