title: ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer.
abstract: Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation.
authors.affiliation: Origins of Cancer Program, Centenary Institute, Camperdown, New South Wales, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: M
authors.initials: M
authors.lastname: van Geldermalsen
authors.affiliation: Origins of Cancer Program, Centenary Institute, Camperdown, New South Wales, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Origins of Cancer Program, Centenary Institute, Camperdown, New South Wales, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Nagarajah
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: A D
authors.initials: AD
authors.lastname: Marshall
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Thoeng
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Bioinformatics Laboratory, Centenary Institute, Camperdown, New South Wales, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Gao
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Bioinformatics Laboratory, Centenary Institute, Camperdown, New South Wales, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Ritchie
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: C G
authors.initials: CG
authors.lastname: Bailey
authors.affiliation: The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Deng
authors.affiliation: The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Harvey
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Beith
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: C I
authors.initials: CI
authors.lastname: Selinger
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: O'Toole
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: J E J
authors.initials: JE
authors.lastname: Rasko
authors.affiliation: Origins of Cancer Program, Centenary Institute, Camperdown, New South Wales, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Holst
mesh_terms: D026962:Amino Acid Transport System ASC / Q000378:metabolism*; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D018295:Neoplasms, Basal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D026962:Amino Acid Transport System ASC; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; D005973:Glutamine