Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer.
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Date
2019-06-18ICR Author
Author
Morotti, M
Bridges, E
Valli, A
Choudhry, H
Sheldon, H
Wigfield, S
Gray, N
Zois, CE
Grimm, F
Jones, D
Teoh, EJ
Cheng, W-C
Lord, S
Anastasiou, D
Haider, S
McIntyre, A
Goberdhan, DCI
Buffa, F
Harris, AL
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Animals
Humans
Mice
Breast Neoplasms
Estrogen Receptor Modulators
Amino Acid Transport System A
Estrogen Receptor alpha
Antineoplastic Agents, Hormonal
Cell Hypoxia
Drug Resistance, Neoplasm
Female
Tumor Microenvironment
Heterografts
Language
eng
Date accepted
2019-05-31
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (25), pp. 12452 - 12461
Publisher
NATL ACAD SCIENCES