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..
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E-Artikel |
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Erscheinungsjahr: |
2010 |
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Erschienen: |
2010 |
Enthalten in: |
Zur Gesamtaufnahme - volume:127 |
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Enthalten in: |
Breast cancer research and treatment - 127(2010), 2 vom: 03. Juli, Seite 375-384 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Gökmen-Polar, Yesim [VerfasserIn] |
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Links: |
Volltext [lizenzpflichtig] |
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Anmerkungen: |
© Springer Science+Business Media, LLC. 2010 |
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doi: |
10.1007/s10549-010-1004-y |
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funding: |
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PPN (Katalog-ID): |
OLC2111926558 |
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520 | |a 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. | ||
650 | 4 | |a EphA2 | |
650 | 4 | |a Estrogen receptor | |
650 | 4 | |a Breast cancer | |
650 | 4 | |a Tamoxifen sensitivity | |
700 | 1 | |a Toroni, Rachel A. |4 aut | |
700 | 1 | |a Hocevar, Barbara A. |4 aut | |
700 | 1 | |a Badve, Sunil |4 aut | |
700 | 1 | |a Zhao, Qianqian |4 aut | |
700 | 1 | |a Shen, Changyu |4 aut | |
700 | 1 | |a Bruckheimer, Elizabeth |4 aut | |
700 | 1 | |a Kinch, Michael S. |4 aut | |
700 | 1 | |a Miller, Kathy D. |4 aut | |
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