The multifaceted roles of Eph/ephrin signaling in breast cancer

Kaenel, Philip; Mosimann, Mischa; Andres, Anne‐Catherine

doi:10.4161/cam.20154

Cited by 50 publications

(43 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Eph receptors require direct cell-to-cell interaction for activation and they are divided into EphA and EphB receptor classes, depending on their preferential binding affinity for ephrinA or ephrinB ligands. Eph receptors have been documented in cancer (51), but the ligands have not been thoroughly investigated and in particular there is limited data on ephrinB1. However, a recent study has shown that enhanced expression of ephrinB1 is associated with lymph node metastasis and poor prognosis in breast cancer (52).…”

Section: Discussionmentioning

confidence: 99%

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Dun

Chalkley

Faulkner

et al. 2015

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up-or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up-(36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and L-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation. Brain metastases affect 10 -20% of cancer patients with disseminated disease (1). Even small lesions can cause neurological disability, and the median survival time of patients with brain metastases is short, with about 80% mortality within one year of diagnosis. The molecular basis of cancer metastases to the brain remains unknown and with advances in the control of systemic disease, the incidence of brain metastases is increasing (1, 2). In the case of breast cancer, brain relapse typically occurs years after primary tumor excision, suggesting that disseminated breast cancer cells must first acquire specialized functions to invade and grow in this organ (3). Retrospective studies of breast cancer patients with brain metastases found that a young age at diagnosis, primary tumors that are estrogen receptor negative or overexpressing the human epidermal growth factor receptor 2 (HER2) 1 and/or epidermal growth factor receptor, and the From the ‡School

show abstract

Section: Discussionmentioning

confidence: 99%

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Dun

Chalkley

Faulkner

et al. 2015

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…The Ephrin-A/EFNA subfamily of ligands is displayed on the cell surface via a glycosyl phosphatidylinositol (GPI) anchor (18). The ability of GPI-anchored proteins to internalize has been debated, yet several clinical-stage ADCs target such proteins (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

“…Reverse signaling to the ligand (Ephrin)-expressing cell can accompany forward signaling to the Eph-expressing cell; however, the mechanisms underlying these signaling cascades remain unclear (17)(18)(19). The Ephrin/Eph family is implicated in breast cancer, where expression of several members inversely correlates with survival (18,20). These observations, coupled with the established role of Eph signaling in cancer, have resulted in numerous targeted therapeutics that have advanced to clinical trials; the majority of which are tyrosine kinase inhibitors (TKI; refs.…”

Section: Introductionmentioning

confidence: 99%

Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions

Damelin

Bankovich²,

Park³

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.Experimental Design: A panel of well-annotated patientderived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for overexpressed antigens, one of which was selected to be the target of an antibody-drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification.Results: We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well-annotated, low-passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor subclassification.Conclusions: These findings demonstrate the potential of PF-06647263 (anti-EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacologic evaluation of the compound, and translational studies to inform clinical development.

show abstract

“…This has led to a hypothesis that ephrinB2 mediated EphB4 activation and a balanced expression of receptor and ligand lead to tumor suppression [16]. This hypothesis was further supported by Noren et al, in which they reported activation of a tumor suppressor signaling pathway, Abl-Crk, downstream of ephrinB2/EphB4 signaling in breast cancer cells [17].…”

Section: Introductionmentioning

confidence: 95%

EphB4 Tyrosine Kinase Stimulation Inhibits Growth of MDA-MB-231 Breast Cancer Cells in a Dose and Time Dependent Manner

et al. 2013

View full text Add to dashboard Cite

Background. EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc. Methods. Cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinB2-Fc. Cell viability was measured on days 3 and 6 following treatment using alamar-blue when cells were in different states of confluence. Results. Stimulation of cells with ephrinB2 did not pose any significant effect on cell viability before reaching confluence, while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose-dependent manner. EphrinB2 treatment did not affect tubular formation and invasion on matrigel. Conclusion. This study showed that EphB4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth-inhibitory properties of EphB4 receptor. It is concluded that growth inhibition has occurred possibly due to long treatment with ligand, a process which leads to receptor downregulation.

show abstract

The multifaceted roles of Eph/ephrin signaling in breast cancer

Cited by 50 publications

References 73 publications

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions

EphB4 Tyrosine Kinase Stimulation Inhibits Growth of MDA-MB-231 Breast Cancer Cells in a Dose and Time Dependent Manner

Contact Info

Product

Resources

About