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.
Highlights
According to the American Cancer Society, 207,090 new cases of invasive breast cancer were anticipated for women in the U.S during 2010
Elevated RNA expression of many Eph receptor tyrosine kinases (RTKs) significantly correlates with poor outcome in human breast cancer
We did not observe any positive or negative associations between expression level and clinical outcome for other Eph RTK family members analyzed, nor did we observe any significant associations between any ephrin ligand family member expression and outcome
Summary
According to the American Cancer Society, 207,090 new cases of invasive breast cancer were anticipated for women in the U.S during 2010. Breast cancer is the second most frequently diagnosed cancer in U.S women, predicted to result in 39,840 deaths in 2010, and ranks second as a cause of cancer death in women (ACS, Breast Cancer Facts and Figures 2010 Atlanta, GA). Understanding the molecular mechanisms that regulate progression of this devastating disease is crucial for identifying novel therapeutic targets. Current treatment options, such as adjuvant chemotherapy or radiation, have improved survival, in women diagnosed with early stage breast cancer (ACS, Breast Cancer Facts and Figures 2010 Atlanta, GA). One of the proposed benefits for new, molecularly targeted therapies is the potential to reduce morbidity associated with cancer as well as mortality
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