Abstract
BackgroundBreast cancer is one of the leading causes of women's death worldwide. It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood.MethodsPlasma proteomes obtained from 6 breast cancer patients and 6 normal healthy women were analyzed by using the isotope-coded affinity tag (ICAT) labeling approach and tandem mass spectrometry. All the plasma samples used were depleted of highly abundant 6 plasma proteins by immune-affinity column chromatography before ICAT labeling. Several proteins showing differential abundance level were selected based on literature searches and their specificity to the commercially available antibodies, and then verified by immunoblot assays.ResultsA total of 155 proteins were identified and quantified by ICAT method. Among them, 33 proteins showed abundance changes by more than 1.5-fold between the plasmas of breast cancer patients and healthy women. We chose 5 proteins for the follow-up confirmation in the individual plasma samples using immunoblot assay. Four proteins, α1-acid glycoprotein 2, monocyte differentiation antigen CD14, biotinidase (BTD), and glutathione peroxidase 3, showed similar abundance ratio to ICAT result. Using a blind set of plasmas obtained from 21 breast cancer patients and 21 normal healthy controls, we confirmed that BTD was significantly down-regulated in breast cancer plasma (Wilcoxon rank-sum test, p = 0.002). BTD levels were lowered in all cancer grades (I-IV) except cancer grade zero. The area under the receiver operating characteristic curve of BTD was 0.78. Estrogen receptor status (p = 0.940) and progesterone receptor status (p = 0.440) were not associated with the plasma BTD levels.ConclusionsOur study suggests that BTD is a potential serological biomarker for the detection of breast cancer.
Highlights
Breast cancer is one of the leading causes of women's death worldwide
isotope-coded affinity tag (ICAT) labeling and sample preparation A pooled plasma sample from 6 breast cancer patients was labeled with a 'heavy (H)' ICAT reagent (Applied Biosystems, Framingham, MA, USA), whilst another pooled sample from 6 normal healthy women was labeled with a 'light (L)' reagent
Analyzing the ICAT-labeled tryptic peptides by LC-MS/MS, a total of 155 proteins were confidently identified by matching MS/MS data (646 unique peptides) to the peptide sequences in human IPI database
Summary
It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood. Any proteome source can be used in the discovery phase, biomarkers that are detected and validated in specimens obtained by less invasive techniques, such as plasma or serum, are more desirable [8,9]. The blood serum or plasma contains enormous complexity of biological components which reflect spatio-temperal changes of diseased cells, tissues, or organs [10]. Knowing any change in the containment of blood caused by a specific disease like cancer will help us understand and develop detection and further management of the disease
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