Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer. 2060 65