Lowered circulating aspartate is a metabolic feature of human breast cancer

Distinct metabolic transformation is essential for cancer cells to sustain a high rate of proliferation and resist cell death signals. Such a metabolic transformation results in unique cellular metabolic phenotypes that are often reflected by distinct metabolite signatures in tumor tissues as well as circulating blood. Using a metabolomics platform, we find that breast cancer is associated with significantly (p = 6.27E-13) lowered plasma aspartate levels in a training group comprising 35 breast cancer patients and 35 controls. The result was validated with 103 plasma samples and 183 serum samples of two groups of primary breast cancer patients. Such a lowered aspartate level is specific to breast cancer as it has shown 0% sensitivity in serum from gastric (n = 114) and colorectal (n = 101) cancer patients. There was a significantly higher level of aspartate in breast cancer tissues (n = 20) than in adjacent non-tumor tissues, and in MCF-7 breast cancer cell line than in MCF-10A cell lines, suggesting that the depleted level of aspartate in blood of breast cancer patients is due to increased tumor aspartate utilization. Together, these findings suggest that lowed circulating aspartate is a key metabolic feature of human breast cancer.

[1]  I. Wilson,et al.  A multi-analytical platform approach to the metabonomic analysis of plasma from normal and Zucker (fa/fa) obese rats. , 2006, Molecular bioSystems.

[2]  W. Mikulits,et al.  Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells. , 2007, Carcinogenesis.

[3]  M. Asaka,et al.  Enhanced expression of asparagine synthetase under glucose-deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and cisplatin. , 2007, Cancer research.

[4]  W. Jia,et al.  An optimized procedure for metabonomic analysis of rat liver tissue using gas chromatography/time-of-flight mass spectrometry. , 2010, Journal of pharmaceutical and biomedical analysis.

[5]  Edward Ng,et al.  BREAST IMAGING SYSTEMS: A REVIEW AND COMPARATIVE STUDY , 2010 .

[6]  Wei Jia,et al.  Urinary Metabolite Markers of Precocious Puberty* , 2011, Molecular & Cellular Proteomics.

[7]  Li-Yan Xu,et al.  A Combined Proteomics and Metabolomics Profiling of Gastric Cardia Cancer Reveals Characteristic Dysregulations in Glucose Metabolism* , 2010, Molecular & Cellular Proteomics.

[8]  Ralph J Deberardinis,et al.  Brick by brick: metabolism and tumor cell growth. , 2008, Current opinion in genetics & development.

[9]  G. Xie,et al.  Waterborne manganese exposure alters plasma, brain, and liver metabolites accompanied by changes in stereotypic behaviors. , 2012, Neurotoxicology and teratology.

[10]  Tianlu Chen,et al.  Serum metabolite profiling of human colorectal cancer using GC-TOFMS and UPLC-QTOFMS. , 2009, Journal of proteome research.

[11]  R. Kiessling,et al.  Tumor-dependent increase of serum amino acid levels in breast cancer patients has diagnostic potential and correlates with molecular tumor subtypes , 2013, Journal of Translational Medicine.

[12]  Ping Liu,et al.  Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma* , 2011, Molecular & Cellular Proteomics.

[13]  P. Skaane Studies comparing screen-film mammography and full-field digital mammography in breast cancer screening: Updated review , 2009, Acta radiologica.

[14]  Wei Jia,et al.  Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteers. , 2009, Journal of proteome research.

[15]  Jordi Oliver,et al.  Breast and lung cancer are associated with a decrease in blood cell amino acid content. , 2003, The Journal of nutritional biochemistry.

[16]  Tianlu Chen,et al.  Salivary metabolite signatures of oral cancer and leukoplakia , 2011, International journal of cancer.

[17]  Kishore K. Pasikanti,et al.  Noninvasive urinary metabonomic diagnosis of human bladder cancer. , 2010, Journal of proteome research.

[18]  G. Xie,et al.  Characterization of pu-erh tea using chemical and metabolic profiling approaches. , 2009, Journal of agricultural and food chemistry.

[19]  Tianlu Chen,et al.  Urinary metabonomic study on colorectal cancer. , 2010, Journal of proteome research.

[20]  Xiaohua Wu,et al.  Serum 27-nor-5β-cholestane-3,7,12,24,25 pentol glucuronide discovered by metabolomics as potential diagnostic biomarker for epithelium ovarian cancer. , 2011, Journal of proteome research.

[21]  S. Wold,et al.  Orthogonal projections to latent structures (O‐PLS) , 2002 .

[22]  K. Wada,et al.  Plasma amino acid profiles are associated with biomarkers of breast cancer risk in premenopausal Japanese women , 2013, Cancer Causes & Control.

[23]  Thomas Szyperski,et al.  Diagnosis of early stage ovarian cancer by 1H NMR metabonomics of serum explored by use of a microflow NMR probe. , 2011, Journal of proteome research.

[24]  P. Meleady,et al.  Proteomic approaches for serum biomarker discovery in cancer. , 2007, Anticancer research.

[25]  Daniel Raftery,et al.  Early detection of recurrent breast cancer using metabolite profiling. , 2010, Cancer research.

[26]  A. Lane,et al.  Targeting aspartate aminotransferase in breast cancer , 2008, Breast Cancer Research.

[27]  Y. Yen,et al.  Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients , 2013, International journal of molecular sciences.

[28]  G. Xie,et al.  Chronic ethanol consumption alters mammalian gastrointestinal content metabolites. , 2013, Journal of proteome research.

[29]  H. Kölbl,et al.  Serum proteome profiling of primary breast cancer indicates a specific biomarker profile. , 2011, Oncology reports.

[30]  Frederic D Sigoillot,et al.  Breakdown of the regulatory control of pyrimidine biosynthesis in human breast cancer cells , 2004, International journal of cancer.

[31]  T. Bathen,et al.  Quantification of metabolites in breast cancer patients with different clinical prognosis using HR MAS MR spectroscopy , 2010, NMR in biomedicine.