Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer
Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α (ERα) positive 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 freque...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
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National Academy of Sciences
2019
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| _version_ | 1826304784135618560 |
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| author | Morotti, M Bridges, E Valli, A Choudhry, H Sheldon, H Wigfield, S Gray, N Zois, C Grimm, F Jones, D Teoh, EJ Wei-Chen, C Anastasiou, D Haider, S McIntyre, A Goberdhan, DCI Buffa, F Harris, AL Lord, SR |
| author_facet | Morotti, M Bridges, E Valli, A Choudhry, H Sheldon, H Wigfield, S Gray, N Zois, C Grimm, F Jones, D Teoh, EJ Wei-Chen, C Anastasiou, D Haider, S McIntyre, A Goberdhan, DCI Buffa, F Harris, AL Lord, SR |
| author_sort | Morotti, M |
| collection | OXFORD |
| description | Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α (ERα) positive 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 it 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 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 downregulation 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 upregulation in-vivo caused complete resistance to anti-estrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlate with hypoxia profiles and worse outcome in patients given anti-estrogen 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. |
| first_indexed | 2024-03-07T06:23:01Z |
| format | Journal article |
| id | oxford-uuid:f34eea20-0dcb-41ad-92ae-016288664e3c |
| institution | University of Oxford |
| last_indexed | 2024-03-07T06:23:01Z |
| publishDate | 2019 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:f34eea20-0dcb-41ad-92ae-016288664e3c2022-03-27T12:11:24ZHypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f34eea20-0dcb-41ad-92ae-016288664e3cSymplectic Elements at OxfordNational Academy of Sciences2019Morotti, MBridges, EValli, AChoudhry, HSheldon, HWigfield, SGray, NZois, CGrimm, FJones, DTeoh, EJWei-Chen, CAnastasiou, DHaider, SMcIntyre, AGoberdhan, DCIBuffa, FHarris, ALLord, SRTumor hypoxia is associated with poor patient outcomes in estrogen receptor-α (ERα) positive 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 it 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 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 downregulation 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 upregulation in-vivo caused complete resistance to anti-estrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlate with hypoxia profiles and worse outcome in patients given anti-estrogen 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. |
| spellingShingle | Morotti, M Bridges, E Valli, A Choudhry, H Sheldon, H Wigfield, S Gray, N Zois, C Grimm, F Jones, D Teoh, EJ Wei-Chen, C Anastasiou, D Haider, S McIntyre, A Goberdhan, DCI Buffa, F Harris, AL Lord, SR Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer |
| title | Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer |
| title_full | Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer |
| title_fullStr | Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer |
| title_full_unstemmed | Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer |
| title_short | Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer |
| title_sort | hypoxia induced switch in snat2 slc38a2 regulation generates endocrine resistance in breast cancer |
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