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The prognostic value of JUNB-positive CTCs in metastatic breast cancer: from bioinformatics to phenotypic characterization
- Source :
- Breast Cancer Research, Vol 21, Iss 1, Pp 1-13 (2019), Breast Cancer Research : BCR
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Background Circulating tumor cells (CTCs) are important for metastatic dissemination of cancer. They can provide useful information, regarding biological features and tumor heterogeneity; however, their detection and characterization are difficult due to their limited number in the bloodstream and their mesenchymal characteristics. Therefore, new biomarkers are needed to address these questions. Methods Bioinformatics functional enrichment analysis revealed a subgroup of 24 genes, potentially overexpressed in CTCs. Among these genes, the chemokine receptor CXCR4 plays a central role. After prioritization according to the CXCR4 corresponding pathways, five molecules (JUNB, YWHAB, TYROBP, NFYA, and PRDX1) were selected for further analysis in biological samples. The SKBR3, MDA-MB231, and MCF7 cell lines, as well as PBMCs from normal (n = 10) blood donors, were used as controls to define the expression pattern of all the examined molecules. Consequently, 100 previously untreated metastatic breast cancer (mBC) patients (n = 100) were analyzed using the following combinations of antibodies: CK (cytokeratin)/CXCR4/JUNB, CK/NFYA/ΥWHΑΒ (14-3-3), and CK/TYROBP/PRDX1. A threshold value for every molecule was considered the mean expression in normal PBMCs. Results Quantification of CXCR4 revealed overexpression of the receptor in SKBR3 and in CTCs, following the subsequent scale (SKBR3>CTCs>Hela>MCF7>MDA-MB231). JUNB was also overexpressed in CTCs (SKBR3>CTCs>MCF7>MDA-MB231>Hela). According to the defined threshold for each molecule, CXCR4-positive CTCs were identified in 90% of the patients with detectable tumor cells in their blood. In addition, 65%, 75%, 14.3%, and 12.5% of the patients harbored JUNB-, TYROBP-, NFYA-, and PRDX-positive CTCs, respectively. Conversely, none of the patients revealed YWHAB-positive CTCs. Interestingly, JUNB expression in CTCs was phenotypically and statistically enhanced compared to patients’ blood cells (p = 0.002) providing a possible new biomarker for CTCs. Furthermore, the detection of JUNB-positive CTCs in patients was associated with poorer PFS (p = 0.015) and OS (p = 0.002). Moreover, JUNB staining of 11 primary and 4 metastatic tumors from the same cohort of patients revealed a dramatic increase of JUNB expression in metastasis. Conclusions CXCR4, JUNB, and TYROBP were overexpressed in CTCs, but only the expression of JUNB was associated with poor prognosis, providing a new biomarker and a potential therapeutic target for the elimination of CTCs. Electronic supplementary material The online version of this article (10.1186/s13058-019-1166-4) contains supplementary material, which is available to authorized users.
- Subjects :
- Receptors, CXCR4
Bioinformatics
JUNB
Breast Neoplasms
lcsh:RC254-282
CXCR4
Metastasis
03 medical and health sciences
Cytokeratin
Breast cancer
0302 clinical medicine
Circulating tumor cell
Cell Line, Tumor
Biomarkers, Tumor
Humans
Medicine
skin and connective tissue diseases
Aged
Neoplasm Staging
Aged, 80 and over
business.industry
Gene Expression Profiling
Computational Biology
Cancer
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Survival Analysis
Metastatic breast cancer
Phenotype
030220 oncology & carcinogenesis
Biomarker (medicine)
Female
Neoplasm Grading
CTCs
Transcriptome
business
Transcription Factors
Research Article
Subjects
Details
- ISSN :
- 1465542X
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research
- Accession number :
- edsair.doi.dedup.....a8c6a231c7363907216a7f129801f44c