The corepressor-associated protein Tab2 as a new target to revert resistance to antiestrogens in breast cancer.

Pharmacological resistance is a serious challenge for all kind of cancers. In hormone-dependent breast cancer, the problem of resistance to endocrine treatments is alleviated by availability of different classes of drugs (SERM, aromatase inhibitors, pure antiestrogen). Nonetheless, understanding the mechanisms of resistance would significantly improve our ability to cure this disease. At the cellular level, the efficacy of antiestrogenic drugs consists primarily in contrasting the transcriptional action of estrogen-activated estrogen receptors (ER). The correct balance of transcriptional coactivators and corepressors in cancer cell nuclei plays a major role in antiestrogenic drug response and, in fact, resistant cells often display aberrant corepressor localization or coactivator overexpression. The Tab2 protein was recently reported in complex with the NCoR corepressor. In response to interleukin, MEKK1 phosphorylates TAb2 and, as a consequence, Tab2 shuttles NCoR to the cytoplasm. This was shown sufficient to convert a steroid hormone antagonist to agonist (Zhu et al. 2006, Cell 124:615-29). Using a series of Tamoxifen (TAM) resistant cells derived from MCF7 by continuous exposure to the drug, we show here that downregulation of Tab2 using a double-strand interfering small RNA restores the antiproliferative response to TAM, indicating that Tab2 is in the pathway leading to TAM resistance in these cells. Interestingly, a similar result was obtained also using the BT474 cell line, which shows amplification and overexpression of the ERBB2 gene. Tab2, together with NCoR, is recruited at estrogen target genes by interaction with the N-terminal domain of ERα (Zhu et al., 2006). By in vitro interaction studies with recombinant proteins, we mapped the interaction of ERα to the central domain of Tab2. In addition, a mimic peptide derived from the N-terminus of ERα, but not a mutated version carrying A/L substitutions, was able to compete for Tab2/ERα interaction. On this basis, we designed a cell permeable peptide, composed of the ERα sequence fused to the Tat minimal carrier domain. Colture of TAMR cells in the presence of the ERα-Tat peptide, but not the mutated version, led to a 40-60 % recovery of the antiproliferative effect of TAM, depending on the cell line or clone. In conclusion, we have identified the Tab2/ ERα interaction as a potential drug target for overcoming TAM resistance in breast cancer.