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Characterization of Survivin Contribution to ErbB2-Mediated Drug Resistance
Overexpression of ErbB2 (Her2/neu) confers poor prognosis to patients with breast cancer. Mechanisms underlying this resistance are poorly understood. Recently, we demonstrated, for the first time, that overexpression of ErbB2 leads to up-regulation of survivin. Expressioon of survivin , an inhibitor of apoptosis (IAP) family member, predicts poor prognosis and resistance to chemo- and radiotherapy in multiple tumor types. Therefore, survivin is likely responsible for at least some of the poor prognostic features conferred by ErbB2 overexpression. HYPOTHESIS: Survivin expression is up-regulated by ErbB2 via PI3-kinase (PI3-K)-Akt and/or Erk1/2 pathways, and contributes to ErbB2-mediated resistance to chemotherapy. Suppression of expression and/or functional activity of survivin will have therapeutic effects against ErbB2-overexpressing breast tumors. SPECIFIC AIM 1. To identify mechanisms of survivin up-regulation in response to ErbB2 overexpression. SPECIFIC AIM 2. To determine the role of survivin in ErbB2-mediated resistance to chemotherapy. SPECIFIC AIM 3. To evaluate therapeutic potential of survivin targeting in ErbB2-overexpressing breast cancer cells. STUDY DESIGN. All in vitro studies in the current proposal will be performed in our MCF-7-derived cell line with inducible overexpression of ErbB2 (MCF-Her29). The effects of ErbB2 overexpression will be assessed after incubation of cells with doxycycline for 48 hours. Uninduced MCF-Her29 cells and two vector-transfected clones will serve as controls. . Specific Aim1 will test whether up-regulation of survivin is controlled at the level of transcription or protein stability and whether inhibition of Akt, NF-kappaB and/or Erk1/2 by chemical inhibitors and siRNA abrogates survivin up-regulation. Specific Aim 2 will determine if down-regulation of survivin expression with siRNA will restore sensitivity of ErbB2-overexpressing cells to chemotherapy. In Specific Aim 3 we will examine, in vitro and in vivo, therapeutic effects of our novel technologies designed to block survivin expression and/or function. The proposed work will expand our knowledge of the mechanisms underlying resistance of ErbB2 positive tumors to chemotherapy and test potential new therapeutic options. The results obtained in this work could be extrapolated to other tumor types that overexpress ErbB2 and/or survivin.
Patients who develop breast tumors with high level of Her2 protein usually have worse prognosis than patients with low levels of Her2 in the tumors. This is at least in part due to resistance of Her2-positive tumors to chemotherapy. The reasons for this resistance are not well understood. We have recently shown that Her2 causes up-regulation of a protein called survivin. Survivin belongs to a family of proteins that protect cells from death. It was shown to make cancer cells resistant to chemo- and radiation therapy and to predict poor prognosis for patients with different types of cancer. We therefore hypothesize that up-regulation of survivin by Her2 contributes to chemotherapy resistance and poor prognosis. One of the aims of this study is to investigate the role which survivin plays in resistance of Her2-positive cells to one of the most efficient chemotherapy drugs, Taxol. Another aim is to study mechanisms by which Her2 up-regulates survivin. In the third part of the study we will use our novel techniques to block survivin functions and determine whether these techniques could improve treatment of Her2-positive breast tumors.