L-arginine dependence of breast cancer - molecular subtypes matter.

IF 3.4 2区 医学 Q2 ONCOLOGY
Juliane Hannemann, Leticia Oliveira-Ferrer, Anne Kathrin Goele, Yoana Mileva, Fiona Kleinsang, Antonia Röglin, Isabell Witzel, Volkmar Müller, Rainer Böger
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引用次数: 0

Abstract

L-arginine limits proliferation in highly proliferative tissues. It is a substrate for nitric oxide synthases, arginases; its methylation by protein-L-arginine methyltransferases (PRMTs) leads to asymmetric (ADMA) and symmetric dimethylarginine (SDMA). We measured L-arginine and its metabolites L-ornithine, L-citrulline, ADMA, and SDMA in a prospective cohort of 243 women with primary breast cancer (BC) and their associations with mortality and disease recurrence during 88 (IQR, 82-93) months of follow-up. We quantified these metabolites and expression of genes involved in L-arginine metabolic pathways in MCF-7, BT-474, SK-BR-3, MDA-MB-231, and MDA-MB-468 cells representing ER-positive, HER2-positive, and triple-negative BC compared to MCF-12 A cells. Plasma L-arginine and ADMA concentrations were elevated in 47 patients with recurrent disease and in 34 non-survivors. ADMA was significantly associated with mortality and recurrent disease in Luminal A patients; low L-citrulline was significantly associated with survival in triple-negative BC. In all BC cells except MCF-7, DDAH1 and DDAH2 expression was higher than in MCF-12 A (DDAH1: 32-44 fold, DDAH2: 1.7-4.2 fold; p < 0.05). By contrast, MCF-7 cells showed low DDAH1 and DDAH2, but high PRMT4 and PRMT6 expression and high L-arginine content. BT-474 and MDA-MB-468 cells showed high ARG2 expression and high L-ornithine concentrations, and MDA-MB-468 cells had the highest L-citrulline/L-arginine ratio. In conclusion, regulation of L-arginine metabolic pathways shows a complex and differential pattern between BC subtypes. ADMA is a prognostic biomarker in Luminal A patients; its metabolizing enzyme, DDAH, is highly overexpressed in BC cells. Thus, fingerprinting of L-arginine metabolism may offer novel personalized treatment options within BC subtypes.

乳腺癌分子亚型对l -精氨酸的依赖性。
l -精氨酸限制高增殖组织的增殖。它是一氧化氮合酶,精氨酸酶的底物;它被蛋白质- l -精氨酸甲基转移酶(PRMTs)甲基化导致不对称(ADMA)和对称二甲基精氨酸(SDMA)。在88个月(IQR, 82-93)个月的随访期间,我们在243名原发性乳腺癌(BC)女性的前瞻性队列中测量了l -精氨酸及其代谢物l -鸟氨酸、l -瓜氨酸、ADMA和SDMA,以及它们与死亡率和疾病复发的关系。与mcf - 12a细胞相比,我们在代表er阳性、her2阳性和三阴性BC的MCF-7、BT-474、SK-BR-3、MDA-MB-231和MDA-MB-468细胞中量化了这些代谢物和参与l -精氨酸代谢途径的基因表达。47例复发性疾病患者和34例非幸存者的血浆l -精氨酸和ADMA浓度升高。ADMA与Luminal A患者的死亡率和复发率显著相关;低l -瓜氨酸与三阴性BC患者的生存率显著相关。在除MCF-7外的所有BC细胞中,DDAH1和DDAH2的表达均高于MCF-12 A (DDAH1: 32-44倍,DDAH2: 1.7-4.2倍;p
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来源期刊
BMC Cancer
BMC Cancer 医学-肿瘤学
CiteScore
6.00
自引率
2.60%
发文量
1204
审稿时长
6.8 months
期刊介绍: BMC Cancer is an open access, peer-reviewed journal that considers articles on all aspects of cancer research, including the pathophysiology, prevention, diagnosis and treatment of cancers. The journal welcomes submissions concerning molecular and cellular biology, genetics, epidemiology, and clinical trials.
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