Dual targeting of EphA2 and ER restores Tamoxifen sensitivity in ER/EphA2-positive breast cancer

Yesim Polar, Rachel A. Toroni, Barbara A. Hocevar, Sunil Badve, Qianqian Zhao, Changyu Shen, Elizabeth Bruckheimer, Michael S. Kinch, Kathy Miller

Research output: Contribution to journalArticle

22 Citations (Scopus)

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-7neo/MCF-7 EphA2 and T47Dneo/T47DEphA2). EA5 inhibits primary tumor growth and restores Tamoxifen sensitivity in the MCF-7 EphA2 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.

Original languageEnglish
Pages (from-to)375-384
Number of pages10
JournalBreast Cancer Research and Treatment
Volume127
Issue number2
DOIs
StatePublished - Jun 2011

Fingerprint

Tamoxifen
Breast Neoplasms
EphA2 Receptor
Ephrins
Cell Line
MCF-7 Cells
Heterografts
Estrogens
Monoclonal Antibodies
Growth
In Vitro Techniques
Neoplasms
Proteins

Keywords

  • Breast cancer
  • EphA2
  • Estrogen receptor
  • Tamoxifen sensitivity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dual targeting of EphA2 and ER restores Tamoxifen sensitivity in ER/EphA2-positive breast cancer. / Polar, Yesim; Toroni, Rachel A.; Hocevar, Barbara A.; Badve, Sunil; Zhao, Qianqian; Shen, Changyu; Bruckheimer, Elizabeth; Kinch, Michael S.; Miller, Kathy.

In: Breast Cancer Research and Treatment, Vol. 127, No. 2, 06.2011, p. 375-384.

Research output: Contribution to journalArticle

Polar, Yesim ; Toroni, Rachel A. ; Hocevar, Barbara A. ; Badve, Sunil ; Zhao, Qianqian ; Shen, Changyu ; Bruckheimer, Elizabeth ; Kinch, Michael S. ; Miller, Kathy. / Dual targeting of EphA2 and ER restores Tamoxifen sensitivity in ER/EphA2-positive breast cancer. In: Breast Cancer Research and Treatment. 2011 ; Vol. 127, No. 2. pp. 375-384.
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