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MYC 对谷氨酰胺-脯氨酸调节轴的调控是管腔 B 型乳腺癌的关键。

MYC regulation of glutamine-proline regulatory axis is key in luminal B breast cancer.

机构信息

Academic Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.

Department of Pathology, Instituto Português de Oncologia do Porto FG, Porto 4200-072, Portugal.

出版信息

Br J Cancer. 2018 Jan;118(2):258-265. doi: 10.1038/bjc.2017.387. Epub 2017 Nov 23.

DOI:10.1038/bjc.2017.387
PMID:29169183
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5785743/
Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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).

CONCLUSIONS

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.

摘要

背景

细胞代谢改变是癌症的一个标志，有些癌症依赖于谷氨酰胺来持续增殖和存活。我们假设谷氨酰胺-脯氨酸调节轴在高增殖性乳腺癌（BC）中具有关键作用。

方法

在大型、特征良好的队列中，评估谷氨酰胺酶（GLS）、吡咯啉-5-羧酸合酶（ALDH18A1）和吡咯啉-5-羧酸还原酶 1（PYCR1）的 DNA/mRNA/蛋白质水平。

结果

PYCR1 拷贝数增加和高 PYCR1 mRNA 与 Luminal B 肿瘤相关。与 ER+/HER2-低增殖类（Luminal A）相比，在雌激素受体（ER）+/人表皮生长因子受体（HER2）-高增殖类（Luminal B）中观察到高 ALDH18A1 和高 GLS 蛋白表达（P=0.030 和 P=0.022），但在 mRNA 中未观察到。谷氨酰胺-脯氨酸调节轴基因的聚类分析显示与 BC 的分子亚型和独立于标准临床病理参数的患者预后显著相关（P=0.012）。在 Luminal B 肿瘤中，只有高 MYC 蛋白与谷氨酰胺-脯氨酸酶的高蛋白表达相关（P<0.001）。

结论

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 luminal BC 的侵袭性亚类中发挥重要作用，因此是一个潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3330/5785743/2c4b92a46127/bjc2017387f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3330/5785743/1097886d48d7/bjc2017387f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3330/5785743/a22ab3ad334a/bjc2017387f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3330/5785743/2c4b92a46127/bjc2017387f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3330/5785743/1097886d48d7/bjc2017387f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3330/5785743/a22ab3ad334a/bjc2017387f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3330/5785743/2c4b92a46127/bjc2017387f3.jpg

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