Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer.

Abstract

Overexpression and altered function of EphA2 receptor tyrosine kinase are critical in the progression of breast cancer and provide a target for breast cancer therapy. We have previously demonstrated that EphA2 overexpression decreases estrogen dependence and Tamoxifen sensitivity both in vitro and in vivo. EA5, a novel monoclonal antibody that mimicks the binding of ephrin A to EphA2, reverses the effect of EphA2 overexpression and restores Tamoxifen sensitivity in EphA2-transfected MCF-7 cells in vitro. To explore the role of EphA2 overexpression on ER-dependent mechanisms, we used two different ER+/EphA2-transfected cell line models (MCF-7(neo)/MCF-7(EphA2) and T47D(neo)/T47D(EphA2)). EA5 inhibits primary tumor growth and restores Tamoxifen sensitivity in the MCF-7(EphA2) xenografts. Using the T47D(EphA2) in vitro model, we verified that EphA2 decreases ER activation in response to E2 stimulation consistent with our earlier results in MCF-7(EphA2) model. We found no direct interaction between ER and EphA2 and no difference in expression of canonical ER-dependent proteins or ER co-regulators. However, E2 stimulation phosphorylates FAK(Tyr925) only in ER+/EphA2+ cell lines. Treatment of T47D(EphA2) cells with EA5 and Tamoxifen leads to dephosphorylation of FAK(Tyr925) in response to E2. Our data demonstrate that dual targeting of EphA2 and ER is a promising approach for delaying resistance to Tamoxifen. The data support our hypothesis that EphA2 impacts ER function via a FAK dependent pathway.

• Authors: Yesim Gökmen-Polar, Rachel A Toroni, Barbara A Hocevar, Sunil Badve, Qianqian Zhao, Changyu Shen, Elizabeth Bruckheimer, Michael S Kinch, Kathy D Miller
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 127 Issue 2 Pg. 375-84 (Jun 2011) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 20602165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents, Hormonal
• Estrogens
• Receptors, Estrogen
• TCF Transcription Factors
• Wnt Proteins
• beta Catenin
• Tamoxifen
• Receptor, EphA2
• Focal Adhesion Kinase 1

Topics

• Animals
• Antibodies, Monoclonal (metabolism, pharmacology)
• Antineoplastic Agents, Hormonal (therapeutic use)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects, genetics)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (drug effects, genetics)
• Estrogens (pharmacology)
• Female
• Focal Adhesion Kinase 1 (metabolism)
• Gene Expression (drug effects, genetics)
• Gene Expression Profiling
• Humans
• Mice
• Mice, Nude
• Phosphorylation (drug effects)
• Receptor, EphA2 (genetics, metabolism)
• Receptors, Estrogen (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• TCF Transcription Factors (genetics)
• Tamoxifen (therapeutic use)
• Wnt Proteins (metabolism)
• beta Catenin (genetics)