MYC regulation of glutamine-proline regulatory axis is key in luminal B breast cancer.
MYC regulation of glutamine-proline regulatory axis is key in luminal B breast cancer.
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MYC调节谷氨酰胺 - 丙啉调节轴是腔内B乳腺癌的关键。
DOI：
10.1038/bjc.2017.387
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发表时间：
2018-01
影响因子：
8.8
通讯作者：
Green AR
中科院分区：
文献类型：
--
作者：
Craze ML;Cheung H;Jewa N;Coimbra NDM;Soria D;El-Ansari R;Aleskandarany MA;Wai Cheng K;Diez-Rodriguez M;Nolan CC;Ellis IO;Rakha EA;Green AR
改变的细胞代谢是癌症的一个标志，一些癌症依赖于谷氨酰胺来维持增殖和存活。我们假设谷氨酰胺-脯氨酸调节轴在高度增殖的乳腺癌（BC）中起关键作用。在大型、充分表征的队列中，在DNA/mRNA/蛋白质水平评估谷氨酰胺酶（GLS）、吡咯啉-5-羧酸合成酶（ALDH 18 A1）和吡咯啉-5-羧酸还原酶1（PYCR 1）。PYCR 1拷贝数的增加和高PYCR 1 mRNA与Luminal B肿瘤相关。与ER+/HER 2-低增殖类别（Luminal A）相比，在雌激素受体（ER）+/人表皮生长因子受体（HER 2）-高增殖类别（Luminal B）中观察到高ALDH 18 A1和高GLS蛋白表达（分别为P=0.030和P=0.022），然而在mRNA中未观察到这一点。谷氨酰胺-脯氨酸调节轴基因的聚类分析显示，与BC的分子亚型和患者预后独立于标准临床病理参数（P=0.012）的显着关联。仅在Luminal B肿瘤中，谷氨酰胺-脯氨酸酶的高蛋白表达均与高MYC蛋白相关（P<0.001）。我们提供了全面的临床数据，表明谷氨酰胺-脯氨酸调节轴在管腔BC的侵袭性亚类中起重要作用，因此是潜在的治疗靶点。
Altered cellular metabolism is a hallmark of cancer and some are reliant on glutamine for sustained proliferation and survival. We hypothesise that the glutamine–proline regulatory axis has a key role in breast cancer (BC) in the highly proliferative classes. Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1), and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at DNA/mRNA/protein levels in large, well-characterised cohorts. Gain of PYCR1 copy number and high PYCR1 mRNA was associated with Luminal B tumours. High ALDH18A1 and high GLS protein expression was observed in the oestrogen receptor (ER)+/human epidermal growth factor receptor (HER2)– high proliferation class (Luminal B) compared with ER+/HER2– low proliferation class (Luminal A) (P=0.030 and P=0.022 respectively), however this was not observed with mRNA. Cluster analysis of the glutamine–proline regulatory axis genes revealed significant associations with molecular subtypes of BC and patient outcome independent of standard clinicopathological parameters (P=0.012). High protein expression of the glutamine–proline enzymes were all associated with high MYC protein in Luminal B tumours only (P<0.001). We provide comprehensive clinical data indicating that the glutamine–proline regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target.