Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer
Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer
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DOI：
10.1016/j.celrep.2019.06.010
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发表时间：
2019-07-02
期刊：
影响因子：
8.8
通讯作者：
Morandi, Andrea
中科院分区：
文献类型：
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作者：
Bacci, Marina;Lorito, Nicla;Morandi, Andrea
内分泌治疗（ET）是雌激素受体阳性（ER +）乳腺癌的标准治疗方法。尽管其有效，但约40%的女性会因对内分泌治疗耐药（ETR）而复发。对ETR细胞的全局转录分析显示，受miR - 23b - 3p表达增强的调控，中性和碱性氨基酸转运体SLC6A14下调，导致氨基酸代谢受损。ETR细胞中这种改变的氨基酸代谢得到自噬激活以及由SLC1A2转运体介导的酸性氨基酸（天冬氨酸和谷氨酸）摄取增强的支持。这些发现的临床意义通过在大量接受ET治疗的患者群体、患者来源的异种移植物以及体内实验中的多种正交方法得到验证。针对这些氨基酸代谢依赖性使ETR细胞对治疗重新敏感，并削弱ETR细胞的侵袭性特征，为对抗或延缓ER +乳腺癌中的ETR提供了预测性生物标志物和潜在的可靶向途径。
Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER+) breast cancers. Despite its efficacy, similar to 40% of women relapse with ET-resistant (ETR) disease. A global transcription analysis in ETR cells reveals a downregulation of the neutral and basic amino acid transporter SLC6A14 governed by enhanced miR-23b-3p expression, resulting in impaired amino acid metabolism. This altered amino acid metabolism in ETR cells is supported by the activation of autophagy and the enhanced import of acidic amino acids (aspartate and glutamate) mediated by the SLC1A2 transporter. The clinical significance of these findings is validated by multiple orthogonal approaches in a large cohort of ET-treated patients, in patient-derived xenografts, and in in vivo experiments. Targeting these amino acid metabolic dependencies resensitizes ETR cells to therapy and impairs the aggressive features of ETR cells, offering predictive biomarkers and potential targetable pathways to be exploited to combat or delay ETR in ER+ breast cancers.