Abstract
BackgroundMetastasis of breast cancer to distal organs is fatal. However, few studies have identified biomarkers that are associated with distant metastatic breast cancer. Furthermore, the inability of current biomarkers, such as HER2, ER, and PR, to differentiate between distant and nondistant metastatic breast cancers accurately has necessitated the development of novel biomarker candidates.MethodsAn integrated proteomics approach that combined filter-aided sample preparation, tandem mass tag labeling (TMT), high pH fractionation, and high-resolution MS was applied to acquire in-depth proteomic data from FFPE distant metastatic breast cancer tissues. A bioinformatics analysis was performed with regard to gene ontology and signaling pathways using differentially expressed proteins (DEPs) to examine the molecular characteristics of distant metastatic breast cancer. In addition, real-time polymerase chain reaction (RT-PCR) and invasion/migration assays were performed to validate the differential regulation and function of our protein targets.ResultsA total of 9441 and 8746 proteins were identified from the pooled and individual sample sets, respectively. Based on our criteria, TUBB2A was selected as a novel biomarker candidate. The metastatic activities of TUBB2A were subsequently validated. In our bioinformatics analysis using DEPs, we characterized the overall molecular features of distant metastasis and measured differences in the molecular functions of distant metastatic breast cancer between breast cancer subtypes.ConclusionsOur report is the first study to examine the distant metastatic breast cancer proteome using FFPE tissues. The depth of our dataset allowed us to discover a novel biomarker candidate and a proteomic characteristics of distant metastatic breast cancer. Distinct molecular features of various breast cancer subtypes were also established. Our proteomic data constitute a valuable resource for research on distant metastatic breast cancer.
Highlights
Metastasis of breast cancer to distal organs is fatal
Our proteomic platform enabled us to perform an indepth analysis of the distant metastatic breast cancer proteome, as evidenced by a dynamic range that spanned over 6 orders of magnitude (Additional file 2: Fig. S3)
Our study demonstrates that the Tandem mass tag (TMT)-based approach is beneficial, because its greater quantitative ability generates a larger selection of proteins from which to choose novel biomarker candidates
Summary
Metastasis of breast cancer to distal organs is fatal. few studies have identified biomarkers that are associated with distant metastatic breast cancer. Distant metastatic breast cancer, which preferentially metastasizes to distal organs, such as the bone, liver, lung, and brain, has a poor prognosis [5, 6] This type of breast cancer causes various complications at the affected sites, such as pericardial effusion, pleural effusion, bone fracture, hypercalcemia, and red blood cell anemia, which worsens survival outcomes [7,8,9]. Distant metastatic breast cancer is assessed, based on various factors, such as tumor size, lymphovascular invasion, histological grade, nodal involvement, and hormone receptor status—all of which are independent risk factors for distant metastatic breast cancer [10,11,12,13] Among these factors, breast cancer molecular subtypes are associated with various patterns of distant metastatic spread and related to differences in survival outcomes [10, 14]. The most widely known molecular subtypes, such as the luminal A, luminal B, HER2, and basal-like (triple-negative) groups, have site-specific, cumulative metastatic incidence rates, demonstrating substantial differences in the distant metastatic behavior of and overall survival between breast cancer subtypes [10]
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