Serum Degradome Markers for the Detection of Breast Cancer

Abstract

Many proteins have been proposed as potential biomarkers for breast cancer. Yet, validation of their discriminative value using quantitative methods has scarcely been performed. In this study, we investigated the discriminative value of six peptides that were previously proposed to be generated by breast cancer specific exoproteases: bradykinin, des-Arg(9)-bradykinin, Hyp(3)-bradykinin, and fragments of fibrinogen alpha-chain (Fib-alpha ([605-629])), complement component 4a (C4a ([1337-1350])), and interalpha trypsin inhibitor heavy chain 4 (ITIH4 ([666-687])). Their absolute serum concentrations were measured with a completely validated liquid chromatography-tandem mass spectrometric assay (LC-MS/MS) and compared between 62 newly diagnosed breast cancer patients and 62 controls matched for age and sample storage duration. Both ITIH4 ([666-687]) and des-Arg(9)-bradykinin showed statistically significantly higher median concentrations in breast cancer samples than in matched control samples. Additionally, we analyzed serum samples collected after surgical removal of the tumor, in which median ITIH4 ([666-687]) and des-Arg(9)-bradykinin concentrations were significantly decreased and not statistically significantly different from concentrations in the controls anymore. In a combined analysis, ITIH4 (666-687]) and des-Arg(9)-bradykinin independently contributed to the discrimination between cases and controls. In this study, we confirmed that the exoprotease breakdown peptides, ITIH4 (666-687]) and des-Arg(9)-bradykinin, differed between breast cancer cases and controls, supporting the potential of degradome markers for the diagnosis of breast cancer.

Serum proteome profiling of primary breast cancer indicates a specific biomarker profile

“…It may be a reliable surrogate tissue for analysis of physiologic or pathologic processes such as cancer. Some studies have addressed the potential of proteomic research to provide serum biomarkers that differentiate breast cancer from benign healthy controls (14)(15)(16)(17)(18)(19). Our results compare well with previously reports by us and others, indicating high sensitivity and specificity when an MS profiling method is used for detecting breast cancer in readily accessible body fluids (20).…”

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

“…ITIH4, a protein secreted by the liver in times of trauma and involved in the acute-phase response, was shown to have a downward trend as the amount of n-3 fatty acids increased in the dietary groups. In serum from breast cancer patients it was shown that this protein as peptide fragments was upregulated in comparison to healthy controls (46,47). ITIH4 has also proposed to be cleaved by plasma kallikrein in cancers such as ovarian and breast (47,48) which could possibly explain the bands seen at 120 kDa (data not shown) and 100 kDa.…”

Proteomic studies in breast cancer (Review)

“…However, in later studies, the increase in cancer cases of the 8.1 kDa marker was not found to be noteworthy, and the 8.9 kDa marker was reported to have decreased in metastatic recurrences (39). Additionally, the ITIH4 (4.3 kDa) fragment has been found to be increased in cancer cases (40,41). Thus, the value of these three biomarkers in the diagnosis of breast cancer remains controversial.…”