Eph/Ephrin Profiling in Human Breast Cancer Reveals Significant Associations between Expression Level and Clinical Outcome

Abstract

Pre-clinical studies provide compelling evidence that Eph family receptor tyrosine kinases (RTKs) and ligands promote cancer growth, neovascularization, invasion, and metastasis. Tumor suppressive roles have also been reported for the receptors, however, creating a potential barrier for clinical application. Determining how these observations relate to clinical outcome is a crucial step for translating the biological and mechanistic data into new molecularly targeted therapies. We investigated eph and ephrin expression in human breast cancer relative to endpoints of overall and/or recurrence-free survival in large microarray datasets. We also investigated protein expression in commercial human breast tissue microarrays (TMA) and Stage I prognostic TMAs linked to recurrence outcome data. We found significant correlations between ephA2, ephA4, ephA7, ephB4, and ephB6 and overall and/or recurrence-free survival in large microarray datasets. Protein expression in TMAs supported these trends. While observed no correlation between ephrin ligand expression and clinical outcome in microarray datasets, ephrin-A1 and EphA2 protein co-expression was significantly associated with recurrence in Stage I prognostic breast cancer TMAs. Our data suggest that several Eph family members are clinically relevant and tractable targets for intervention in human breast cancer. Moreover, profiling Eph receptor expression patterns in the context of relevant ligands and in the context of stage may be valuable in terms of diagnostics and treatment.

Eph receptor and ephrin function in breast, gut, and skin epithelia

“…68 Epigenetic repression of EphA5 was associated with predictors of poor prognoses including high tumor grade, lymph node metastasis, and progesterone receptor negative status indicative of resistance to endocrine therapy. 86 A genome-wide association study of more than 2,000 invasive breast cancer samples and matched controls revealed changes in EphB1, EphA3, and EphA7.…”

“…For example, increased EphA2 expression has been found in aggressive breast cancers and was significantly correlated with decreased overall survival and invasive ductal carcinoma. 68 Although breast ductal carcinomas express EphA2 and ephrin-A1, ligand expression is reduced in corresponding lymph node metastases. Breast carcinoma cell line invasiveness also correlated with a loss of ephrin-A1 and mislocalization of EphA2 in the cytoplasm.…”

Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC

“…Preclinical models provide compelling evidence that EPHA2 overexpression increases breast tumor formation, malignant progression, and therapeutic resistance to antitumor therapies (9,13). Large-scale expression profiling for EPHA2 transcript levels in relation to clinical outcome revealed a negative association between EPHA2 transcript levels and overall survival in breast cancer (14). These findings are consistent with preclinical studies in genetically engineered mouse models of breast cancer, which revealed distinct roles for EPHA2 in the tumor epithelia, in which EPHA2 signaling drives tumor cell proliferation and survival, and in the tumor microenvironment, in which EPHA2 is required for tumor angiogenesis (9,15,16).…”

Profiling Eph receptor expression in cells and tissues

“…1,2 Eph receptor and ephrin expression is also disregulated during cancer progression, and in many cases knowing the expression levels of specific Eph receptors and ephrins could be useful for diagnostic and prognostic purposes. 2,[8][9][10] Profiling Eph receptor and ephrin expression in tumors may also be helpful in the future to design targeted and personalized therapies as well as to assess their effectiveness.…”