Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Yesim Go¨kmen-Polar Rachel A. Toroni Barbara A. Hocevar Sunil Badve Qianqian Zhao Changyu Shen Elizabeth Bruckheimer Michael S. Kinch
- چاپ و سال / کشور: 2010
Description
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-7neo/MCF-7EphA2 and T47Dneo/T47DEphA2). EA5 inhibits primary tumor growth and restores Tamoxifen sensitivity in the MCF- 7EphA2 xenografts. Using the T47DEphA2 in vitro model, we verified that EphA2 decreases ER activation in response to E2 stimulation consistent with our earlier results in MCF- 7EphA2 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 FAKTyr925 only in ER?/ EphA2? cell lines. Treatment of T47DEphA2 cells with EA5 and Tamoxifen leads to dephosphorylation of FAKTyr925 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.
Breast Cancer Res Treat (2011) 127:375–384 Received: 26 March 2010 / Accepted: 17 June 2010 / Published online: 3 July 2010 Springer Science+Business Media, LLC. 2010
