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EphA2 Overexpression Decreases Estrogen Dependence and Tamoxifen Sensitivity¹

Department of Basic Medical Sciences, Purdue University Cancer Center, West Lafayette, Indiana 47907 [M. L.]; Division of Hematology and Oncology, Indiana University, Indianapolis, Indiana 46202 [K. D. M., Y. G-P., M-H. J.]; and MedImmune, Inc., Gaithersburg, Maryland 20878 [M. S. K.]

The EphA2 receptor tyrosine kinase is found at low levels on nontransformed adult breast epithelial cells but is frequently overexpressed on aggressive breast cancer cells. Recent studies have documented an inverse relationship between EphA2 and estrogen receptor expression in breast cancer cell lines. In our present study, we demonstrate that overexpression of EphA2 decreases estrogen dependence as defined using both in vitro and in vivo criteria. The EphA2-transfected cells demonstrate increased growth in vitro and form larger and more aggressive tumors in vivo. EphA2 overexpression also decreases the ability of tamoxifen to inhibit breast cancer cell growth and tumorigenesis. These effects of EphA2 overexpression can be overcome by antibody-based targeting of EphA2. In particular, certain EphA2 antibodies can resensitize EphA2-overexpressing breast tumor cells to tamoxifen. These results have important implications for understanding the molecular basis underlying estrogen dependence and provide further evidence that EphA2 may provide a much-needed therapeutic target for breast cancer.

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