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Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12452-12461. doi: 10.1073/pnas.1818521116. Epub 2019 May 31.

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer.

Author information

1
Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, United Kingdom; drmorottimatteo@gmail.com aharris.lab@imm.ox.ac.uk.
2
Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, United Kingdom.
3
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah F6VM+J2, Saudi Arabia.
4
Computational Biology Research Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
5
Cancer Metabolism Laboratory, Francis Crick Institute, London NW1 1ST, United Kingdom.
6
Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom.
7
The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, United Kingdom.
8
Cancer Biology, Division of Cancer and Stem Cells, The University of Nottingham, Nottingham NG7 2UH, United Kingdom.
9
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.

Abstract

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α-positive (ERα+) 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 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 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.

KEYWORDS:

ERα; amino acid transporter; breast cancer; cancer metabolism; hypoxia

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