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

Research output: Contribution to journalArticle

  • External authors:
  • Marina Bacci
  • Nicla Lorito
  • Luiga Ippolito
  • Matteo Ramazzotti
  • Simone Luti
  • Simone Romagnoli
  • Matteo Parri
  • Francesca Bianchini
  • Federica Cappellesso
  • Federico Virga
  • Qiong Gao
  • Elisabetta Marangoni
  • Lesley-Ann Martin
  • Giuseppina Comito
  • Manuela Ferracin
  • Elisa Giannoni
  • Massimiliano Mazzone
  • Paola Chiarugi
  • Andrea Morandi

Abstract

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)104-118
JournalCell Reports
Volume28
Issue number1
DOIs
Publication statusPublished - 2 Jul 2019