Multiple epigenetic programs creating aberrant transcription contribute to the development of breast cancer. Triple negative breast cancer, common in young and African American women has a group of essential genes silenced by DNA hypermethylation that contribute to the poorer prognosis basal phenotype. We believe that specific epigenetic targets that contribute to the development of breast cancer, once identified, will lead to a novel approach to the treatment of this disease. To this end we targeted the disruption of the PAH2 domain of the Sin3 co-repressor that binds to a small group of transcription factors that contain a specific motif called SID (mSin3A interaction domain) using SID decoys. Sin3 serves as a multisubunit corepressor scaffold protein that regulates transcription by recruiting HDAC, BP2/JARID1A, a demethylase specific for di- and trimethylated lysine 4 of histone H3, critical for de novo DNA methylations and other chromatin modifiers. The disruption of PAH2 domain of Sin3 binding to a limited number of SID transcription factors including REST, MAD1, KLF-9, -10, -11, -13 and -16, UME6 and HBP predicts a more selective epigenetic effect than treatment with HDAC inhibitors or demethylating agents. Our data demonstrate that transfection of the minimal SID or treatment with the encoded 13 amino acid peptide (SID peptide) disrupts SID transcription factor binding to the Sin3A PAH2 domain induces profound phenotypic changes of morphogenesis, loss of invasion, contact inhibition in triple negative human and mouse breast cancer models in vitro and in vivo. This switch from a basal to a more differentiated luminal phenotype involves epigenetic reprogramming contributing to re-expression of Ecadherin, estrogen and retinoic acid receptors (ER and RARs) adds support to the hypothesis of reversion of the Epithelial/Mesenchymal Transition (EMT). This was observed in 3 triple negative but not in 2 ER positive breast cancer cell lines. Moreover, in the human triple- negative cell lines the responsiveness to estrogen, tamoxifen and RAR agonists is restored. Tumor growth is inhibited (70%) when tumor cells obtained from the tumors generated in the MMTV-myc transgenic models were transfected with the SID decoy and inoculated orthotopically in FVB mice. Our ongoing research is to develop stable SID peptide and small molecule inhibitors and evaluate in vitro in a large number of breast cancer cell lines to establish triple negative specificity and parameters for pre-clinical design. Dissecting the mechanisms and consequences of SID decoy disruption of PAH2-Sin 3 and SID transcription will be studied in depth and should offer new insights in understanding epigenetic regulation of the basal phenotype and insight into the EMT hypothesis in cancer development. This offers other therapeutic options for triple negative breast cancer and also novel druggable targets.
We have used a decoy (SID) to disrupt a specific epigenetic target which induces human triple negative breast cancer cell, morphogenesis, loss of invasion, differentiation, growth inhibition in vivo and restores sensitivity to anti-estrogen. Dissecting the mechanisms and consequences of SID decoy disruption will be studied in depth and should offer new insights in understanding epigenetic regulation of the basal phenotype and insight into breast cancer development. Successful SID decoy development offers other therapeutic options for triple negative breast cancer and also novel drugable targets.
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