Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 25, Pages 12452-12461Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1818521116
Keywords
amino acid transporter; breast cancer; cancer metabolism; ER alpha; hypoxia
Categories
Funding
- Cancer Research UK
- Oxford National Institute of Health Research Biomedical Research Centre
- Breast Cancer Research Foundation
- Oxfordshire Community Foundation
- Fondazione Veronesi fellowship
- Medical Research Council (MRC) [MC_UP_1202/1]
- Francis Crick Institute
- UK MRC
- Wellcome Trust [FC001033]
- MRC [MR/P010334/1, MC_PC_15065, MC_UP_1202/1] Funding Source: UKRI
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Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-alpha-positive (ER alpha(+) 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 ER alpha, but it became predominantly a hypoxia-inducible factor la (HIF-1 alpha)-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1 alpha and ER alpha overlap in SNAT2's cis-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 ER alpha 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 ER alpha and HIF-1 alpha, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.
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