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Session III : Protein kinase cascades as therapeutic targets Poster III, 20
Constitutive active EGFR and Erk1/2 is promising targets for treatment of antiestrogen
resistant breast cancer cell lines
Thomas Frogne, Jan S. Jepsen and Anne E. Lykkesfeldt
Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer
Society Strandboulevarden 49, DK-2100 Copenhagen, Denmark E-mail: tfr@cancer.dk
Breast cancer patients with advanced disease often benefit from endocrine therapy. However,
after an initial response, most patients will develop resistance towards treatment. In our
department, we have established a large panel of antiestrogen resistant cell lines, hereby
mimicking antiestrogen resistant tumor growth. We have previously shown that these cell
lines are dependent on activated Protein Kinase B (PKB/Akt) to maintain growth in the
presence of antiestrogen and we are currently investigating the importance of the ErbB
receptor family. When we compare the parental and resistant cell lines under basal growth
conditions we see an upregulation of the Epidermal Growth Factor Receptor (EGFR) protein
and an increase in activity of the prominent downstream targets Extracellular Regulated
Kinase 1 & 2 (Erk1/2), in our antiestrogen resistant cells. Furthermore, the resistant cell lines
possessed increased activation of ErbB2 and had lost protein expression of ErbB4. To asses
the importance of EGFR and Erk1/2 in growth of the resistant cell lines we used the small
molecule inhibitors ZD1839 and U0126, which inhibits activation of EGFR and Erk1/2,
respectively. These experiments showed a significantly stronger growth inhibition of the
antiestrogen resistant cell lines when compared to parental cells. Further studies with these
inhibitors showed that activation of EGFR and Erk1/2 is not only required for growth of the
antiestogen resistant cell lines but also for the development of antiestrogen resistance.
Based on these observations, we conclude that constitutive activation of EGFR and Erk1/2 is
required for both development and growth of antiestrogen resistant cell lines.
We are currently evaluating expression of activated Akt and Erk1/2 in clinical material in
order to evaluate whether antiestrogen resistant tumors overexpress active Akt and/or Erk1/2
and whether these two kinases may be a target for treatment of antiestrogen resistant breast
cancer.
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