EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity.
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.
Lu
Ming
M
Department of Basic Medical Sciences, Purdue University Cancer Center, West Lafayette, Indiana 47907, USA.
Miller
Kathy D
KD
Gokmen-Polar
Yesim
Y
Jeng
Meei-Huey
MH
Kinch
Michael S
MS
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004967:Estrogens; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013312:Stress, Physiological; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D004958:Estradiol; D036104:Receptor, EphA2