Abstract 2826: Reversal of the basal phenotype in triple negative (TN) breast cancer using a SID decoy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.2826-2826
• Main Authors: Ariztia, Edgardo V., Farias, Eduardo F., Petrie, Kevin, Leibovitch, Boris, Zelent, Arthur, Zhou, Ming-Ming, Waxman, Samuel
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-2826

We have previously reported that site-specific disruption of the Sin3 complex results in targeted epigenetic reprogramming and differentiation in TN breast cancer (Farias et al., PNAS 2010, 107:11811-6). The Sin3 A/B are multidomain adapter proteins part of a multisubunit corepressor scaffold that regulates transcription via the recruitement of HDAC and BP2/JARID1 A. Sin3 (A/B) contain four paired amphipathic α-helices known as PAH domains, a central HID (HDAC interaction domain) also serves as docking platform for a variety of corepressors, a C-terminal domain is a highly conserved region. We have targeted the disruption of the PAH2 domain binding to SID (mSin3A interaction domain) containing transcription factors such as MAD1, REST, KLF-9, -10, -11, -13 and -16, using a peptide decoy containing the SID motif. These studies have been carried out in several breast cancer cell lines including 5 TN, 2 estrogen receptor positive (ER+) and a non-transformed mammary cell line. Transfection with a plasmid expressing minimal SID or treatment with a 13 amino-acid peptide (SID peptide) disrupts transcription factor binding to the PAH2 domain resulting in extreme changes in morphology, cytoskeletal organization, adhesion, decreased extracellular proteolytic activity (MMP-9 and uPA), loss of invasive capacity and anchorage independent growth. There was re-expression of functional E-cadherin, estrogen and retinoic acid receptors. Effects in vivo xenograft also included inhibition of tumor growth and metastasis in FVB mice. 3D cultures in Matrigel have revealed a SID decoy dependent switch from a basal to a more luminal phenotype. These effects of SID decoy occurred in TN but not in ER+ or non-transformed breast cancer cell lines. Taken together, these results support the hypothesis in which SID decoy interference with PAH2 domain binding can revert Epithelial/Mesenchymal Transition in TN breast cancer cells and results in a less malignant phenotype. Fourteen candidate small molecule inhibitors, from a computerized screen of 115,000 compounds, were tested in a mammalian two hybrid assay and some of them have been tested in cellular invasion, proliferation and morphogenesis assays. One of them, compound 14 (C14) has shown no toxicity, induces E-cadherin expression and is effective in inhibiting Matrigel invasion of MDA-MB-231 at 100 nM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Ca