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- W2953231323 abstract "Abstract 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 HIF1α 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 HIF-1α and worse outcome in patients given anti-estrogen therapy. Our findings show a switch in 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." @default.
- W2953231323 created "2019-06-27" @default.
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- W2953231323 date "2018-08-03" @default.
- W2953231323 modified "2023-10-06" @default.
- W2953231323 title "Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine-resistance in breast cancer" @default.
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- W2953231323 doi "https://doi.org/10.1101/384628" @default.
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