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Prognostic value of ephrin B receptors in breast cancer: An online survival analysis using the microarray data of 3,554 patients.

ABSTRACT: The roles of Ephrin B (EphB) receptors in cancer are relatively unknown as these receptors are associated with complex signaling pathways. A limited number of studies have investigated the association between EphB receptors and prognosis. Using the Kaplan-Meier plotter database, the present study investigated the associations between the mRNA expression levels of five EphB receptors and the outcomes of 3,554 patients with breast cancer who had been followed-up for 20 years. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to assess the relative risk of survival. The results demonstrated that high mRNA expression levels of EphB2 (HR, 0.74; 95% CI, 0.66-0.84; P=2.1×10-6), EphB4 (HR, 0.82; 95% CI, 0.72-0.93; P=0.0023) and EphB6 (HR, 0.69; 95% CI, 0.61-0.78; P=3×10-9) were significantly associated with improved survival, while a high mRNA expression level of EphB3 (HR, 1.14; 95% CI, 1.01-1.28; P=0.029) was associated with worse survival for patients with breast cancer. High expression levels of all EphB receptors, including EphB1 (HR, 1.4; 95% CI, 1.02-1.94; P=0.039), EphB2 (HR, 1.34; 95% CI, 1.07-1.67; P=0.011), EphB3 (HR, 1.39; 95% CI, 1.11-1.73, P=0.0038), EphB4 (HR, 1.33; 95% CI, 1.06-1.67; P=0.013) and EphB6 (HR, 1.32; 95% CI, 1.05-1.65; P=0.016), were associated with an increased risk of mortality in patients with lymph-node-positive breast cancer. High mRNA expression levels of EphB1 were not associated with survival for all patients with breast cancer (HR, 0.85; 95% CI, 0.72-1.01; P=0.058). The results of the present suggested that EphB receptors may be useful as prognostic biomarkers of breast cancer.

SUBMITTER: Mu X

PROVIDER: S-EPMC6540016 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Prognostic value of ephrin B receptors in breast cancer: An online survival analysis using the microarray data of 3,554 patients.

Mu Xin X Huang Ou O Jiang Min M Xie Zuoquan Z Chen Debo D Zhang Xi X

Oncology letters 20190517 1

The roles of Ephrin B (EphB) receptors in cancer are relatively unknown as these receptors are associated with complex signaling pathways. A limited number of studies have investigated the association between EphB receptors and prognosis. Using the Kaplan-Meier plotter database, the present study investigated the associations between the mRNA expression levels of five EphB receptors and the outcomes of 3,554 patients with breast cancer who had been followed-up for 20 years. Hazard ratios (HR) an ...[more]

PMID: 31289549

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Project description:Cell-cell communication proteins Eph and ephrin constitute the largest family of receptor tyrosine kinases (RTKs). They are distinguished by the fact that both receptors and ligands are membrane-bound, and both can drive intracellular signaling in their respective cells. Ever since these RTKs have been found to be involved in cancer development, strategies to target them therapeutically have been actively pursued. However, before this goal can be rationally achieved, the contributions of either Eph receptors or their ephrin ligands to cancer development and progression should be scrutinized in depth. To assess the clinical pertinence of this concern, we performed a systematic review and meta-analysis of the prognostic/predictive value of EphB2 and its multiple cognate ephrin ligands in breast cancer. We found that EphB2 has prognostic value, as indicated by the association of higher EphB2 expression levels with lower distant metastasis-free survival (DMFS), and the association of lower EphB2 expression levels with poorer relapse-free survival (RFS). We also found that higher EphB2 expression could be a prognostic factor for distant metastasis, specifically in the luminal subtypes of breast cancer. EFNB2 showed a marked correlation between higher expression levels and shorter DMFS. EFNA5 or EFNB1 overexpression is correlated with longer RFS. Increased EFNB1 expression is correlated with longer OS in lymph node (LN)-negative patients and the luminal B subtype. Higher levels of EFNB2 or EFNA5 are significantly correlated with shorter RFS, regardless of LN status. However, while this correlation with shorter RFS is true for EFNB2 in all subtypes except basal, it is also true for EFNA5 in all subtypes except HER2+. The analysis also points to possible predictive value for EphB2. In systemically treated patients who have undergone either endocrine therapy or chemotherapy, we found that higher expression of EphB2 is correlated with better rates of RFS. Bearing in mind the limitations inherent to any mRNA-based profiling method, we complemented our analysis with an immunohistochemical assessment of expression levels of both the EphB2 receptor and cognate ephrin ligands. We found that the latter are significantly more expressed in cancers than in normal tissues, and even more so in invasive and metastatic samples than in ductal carcinoma in situ (DCIS). Finally, in an in vitro cellular model of breast cancer progression, based on H-Ras-transformation of the MCF10A benign mammary cell line, we observed dramatic increases in the mRNA expression of EphB2 receptor and EFNB1 and EFNB2 ligands in transformed and invasive cells in comparison with their benign counterparts. Taken together, these data show the clinical validity of a model whereby EphB2, along with its cognate ephrin ligands, have dual anti- and pro-tumor progression effects. In so doing, they reinforce the necessity of further biological investigations into Ephs and ephrins, prior to using them in targeted therapies.

Project description:Numerous microarray-based prognostic gene expression signatures of primary neoplasms have been published but often with little concurrence between studies, thus limiting their clinical utility. We describe a methodology using logistic regression, which circumvents limitations of conventional Kaplan Meier analysis. We applied this approach to a thrice-analyzed and published squamous cell carcinoma (SQCC) of the lung data set, with the objective of identifying gene expressions predictive of early death versus long survival in early-stage disease. A similar analysis was applied to a data set of triple negative breast carcinoma cases, which present similar clinical challenges.Important to our approach is the selection of homogenous patient groups for comparison. In the lung study, we selected two groups (including only stages I and II), equal in size, of earliest deaths and longest survivors. Genes varying at least four-fold were tested by logistic regression for accuracy of prediction (area under a ROC plot). The gene list was refined by applying two sliding-window analyses and by validations using a leave-one-out approach and model building with validation subsets. In the breast study, a similar logistic regression analysis was used after selecting appropriate cases for comparison.A total of 8594 variable genes were tested for accuracy in predicting earliest deaths versus longest survivors in SQCC. After applying the two sliding window and the leave-one-out analyses, 24 prognostic genes were identified; most of them were B-cell related. When the same data set of stage I and II cases was analyzed using a conventional Kaplan Meier (KM) approach, we identified fewer immune-related genes among the most statistically significant hits; when stage III cases were included, most of the prognostic genes were missed. Interestingly, logistic regression analysis of the breast cancer data set identified many immune-related genes predictive of clinical outcome.Stratification of cases based on clinical data, careful selection of two groups for comparison, and the application of logistic regression analysis substantially improved predictive accuracy in comparison to conventional KM approaches. B cell-related genes dominated the list of prognostic genes in early stage SQCC of the lung and triple negative breast cancer.

Dataset Information

Prognostic value of ephrin B receptors in breast cancer: An online survival analysis using the microarray data of 3,554 patients.

Publications

Prognostic value of ephrin B receptors in breast cancer: An online survival analysis using the microarray data of 3,554 patients.

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