Pharmacological resistance is a serious challenge for all kind of cancer. The correct balance of transcriptional coactivators and corepressors in breast cancer cell has a key role in determining the response to antiestrogenic drug. Coactivator amplification or corepressor failure may even switch the function of antagonists from gene repression to activation. In the case of resistance to sex steroid antagonists caused by inflammation, the mechanisms is based on an evolutionary conserved steroid receptor N-terminal motif, which causes recruitment of Tab2 as a component of the corepressor complex. Tab2 acts as a sensor of the inflammatory pathway and induces dismissal of NCoR corepressor from target genes, inducing resistance to endocrine therapy (Zhu et al. 2006). Using a series of Tamoxifen (TAM) resistant cells, we show that downregulation of Tab2 by RNA interference restores the antiproliferative response to TAM. A mimic peptide derived from the N-terminus of ERα was able to compete for Tab2/ERα interaction in vitro. Therefore, we designed a cell permeable peptide, composed of the ERα sequence fused to the Tat minimal carrier domain. Culture of TAMR cells in the presence of the ERα-Tat peptide led to about 50% recovery of the antiproliferative effect of TAM. This peptide is currently under development as a lead compound for reversal of pharmacological resistance to Tamoxifen in breast cancer. In addition, in order to develop a similar Tab2 mimetic peptide capable of interfering with the ER/Tab2 interaction, we have mapped the interaction of ERα to the central domain of Tab2 by in vitro interaction studies. Microarray results from different clones of Tab2-depleted TAMR cells show 283 modulated genes and Ingenuity Pathway Analysis reveals Cell Cycle as the main regulated molecular network according to the biological assay. In conclusion, we have identified the Tab2/ERα interaction as a potential drug target for overcoming TAM resistance in breast cancer.
The corepressor-associated protein Tab2 as a new target to revert resistance to antiestrogens in breast cancer
REINERI, STEFANIA;CUTRUPI, SANTINA;CAIZZI, LIVIA;RICCI, LAURA;DE BORTOLI, Michele
2011-01-01
Abstract
Pharmacological resistance is a serious challenge for all kind of cancer. The correct balance of transcriptional coactivators and corepressors in breast cancer cell has a key role in determining the response to antiestrogenic drug. Coactivator amplification or corepressor failure may even switch the function of antagonists from gene repression to activation. In the case of resistance to sex steroid antagonists caused by inflammation, the mechanisms is based on an evolutionary conserved steroid receptor N-terminal motif, which causes recruitment of Tab2 as a component of the corepressor complex. Tab2 acts as a sensor of the inflammatory pathway and induces dismissal of NCoR corepressor from target genes, inducing resistance to endocrine therapy (Zhu et al. 2006). Using a series of Tamoxifen (TAM) resistant cells, we show that downregulation of Tab2 by RNA interference restores the antiproliferative response to TAM. A mimic peptide derived from the N-terminus of ERα was able to compete for Tab2/ERα interaction in vitro. Therefore, we designed a cell permeable peptide, composed of the ERα sequence fused to the Tat minimal carrier domain. Culture of TAMR cells in the presence of the ERα-Tat peptide led to about 50% recovery of the antiproliferative effect of TAM. This peptide is currently under development as a lead compound for reversal of pharmacological resistance to Tamoxifen in breast cancer. In addition, in order to develop a similar Tab2 mimetic peptide capable of interfering with the ER/Tab2 interaction, we have mapped the interaction of ERα to the central domain of Tab2 by in vitro interaction studies. Microarray results from different clones of Tab2-depleted TAMR cells show 283 modulated genes and Ingenuity Pathway Analysis reveals Cell Cycle as the main regulated molecular network according to the biological assay. In conclusion, we have identified the Tab2/ERα interaction as a potential drug target for overcoming TAM resistance in breast cancer.
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