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dc.contributor.authorMorotti, M
dc.contributor.authorBridges, E
dc.contributor.authorValli, A
dc.contributor.authorChoudhry, H
dc.contributor.authorSheldon, H
dc.contributor.authorWigfield, S
dc.contributor.authorGray, N
dc.contributor.authorZois, CE
dc.contributor.authorGrimm, F
dc.contributor.authorJones, D
dc.contributor.authorTeoh, EJ
dc.contributor.authorCheng, W-C
dc.contributor.authorLord, S
dc.contributor.authorAnastasiou, D
dc.contributor.authorHaider, S
dc.contributor.authorMcIntyre, A
dc.contributor.authorGoberdhan, DCI
dc.contributor.authorBuffa, F
dc.contributor.authorHarris, AL
dc.date.accessioned2021-06-11T11:39:19Z
dc.date.available2021-06-11T11:39:19Z
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2019, 116 (25), pp. 12452 - 12461
dc.identifier.issn0027-8424
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4623
dc.identifier.eissn1091-6490
dc.identifier.eissn1091-6490en_US
dc.identifier.doi10.1073/pnas.1818521116
dc.identifier.doi10.1073/pnas.1818521116en_US
dc.description.abstractTumor hypoxia is associated with poor patient outcomes in estrogen receptor-α-positive (ERα<sup>+</sup>) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2's <i>cis</i>-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.
dc.formatPrint-Electronic
dc.format.extent12452 - 12461
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectBreast Neoplasms
dc.subjectEstrogen Receptor Modulators
dc.subjectAmino Acid Transport System A
dc.subjectEstrogen Receptor alpha
dc.subjectAntineoplastic Agents, Hormonal
dc.subjectCell Hypoxia
dc.subjectDrug Resistance, Neoplasm
dc.subjectFemale
dc.subjectTumor Microenvironment
dc.subjectHeterografts
dc.titleHypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-05-31
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1073/pnas.1818521116
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
dc.relation.isPartOfProceedings of the National Academy of Sciences of the United States of America
pubs.issue25
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.publication-statusPublished
pubs.volume116en_US
pubs.embargo.termsNot known
dc.contributor.icrauthorHaider, Syeden


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