Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer.
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.
Gökmen-Polar
Yesim
Y
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Toroni
Rachel A
RA
Hocevar
Barbara A
BA
Badve
Sunil
S
Zhao
Qianqian
Q
Shen
Changyu
C
Bruckheimer
Elizabeth
E
Kinch
Michael S
MS
Miller
Kathy D
KD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics; D013629:Tamoxifen / Q000627:therapeutic use*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics
D000911:Antibodies, Monoclonal; D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D011960:Receptors, Estrogen; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D013629:Tamoxifen; D036104:Receptor, EphA2; D051417:Focal Adhesion Kinase 1