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 i...

Full description

Saved in:
Bibliographic Details
Published in:Breast cancer research and treatment 2011-06, Vol.127 (2), p.375-384
Main Authors: Gökmen-Polar, Yesim, Toroni, Rachel A., Hocevar, Barbara A., Badve, Sunil, Zhao, Qianqian, Shen, Changyu, Bruckheimer, Elizabeth, Kinch, Michael S., Miller, Kathy D.
Format: Article
Language:English
Subjects:
Analysis
Animals
Antibodies, Monoclonal - metabolism
Antibodies, Monoclonal - pharmacology
Antineoplastic Agents, Hormonal - therapeutic use
beta Catenin - genetics
Biological and medical sciences
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cancer research
Cancer therapies
Cell Line, Tumor
Cell Movement - drug effects
Cell Movement - genetics
Cell Proliferation - drug effects
Cellular biology
Development and progression
Disease Models, Animal
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Drug therapy
Estrogen
Estrogens - pharmacology
Female
Focal Adhesion Kinase 1 - metabolism
Gene Expression - drug effects
Gene Expression - genetics
Gene Expression Profiling
Gynecology. Andrology. Obstetrics
Health aspects
Humans
Kinases
Mammary gland diseases
Medical sciences
Medicine
Medicine & Public Health
Mice
Mice, Nude
Monoclonal antibodies
Oncology
Phosphorylation - drug effects
Preclinical Study
Proteins
Receptor, EphA2 - genetics
Receptor, EphA2 - metabolism
Receptors, Estrogen - genetics
Receptors, Estrogen - metabolism
Signal Transduction - drug effects
Signal Transduction - genetics
Tamoxifen
Tamoxifen - therapeutic use
TCF Transcription Factors - genetics
Toy industry
Tumors
Wnt Proteins - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0167-6806
1573-7217
DOI:10.1007/s10549-010-1004-y