Abstract 285: Uncovering the disorder of breast invasive carcinoma homeostasis proteins

Abstract

Abstract Breast cancer is one of the most common cancers among women worldwide. Recent studies suggest that cancer cell homeostatic stable phenotypes may be implemented, controlled and maintained by Master Regulators (MR) proteins. In essence, all MR proteins are Transcription Factors, which frequently are intrinsically (IDP) or partially disordered proteins, depending on the extent of disordered regions (IDRs). IDPs/IDRs are known to be promiscuous binders that commonly function as central hubs in protein networks. Furthermore, they contain Molecular Recognition Features (MoRFs) and/or Short Linear Motifs (SLiMs), regions that occupy a unique structural and functional niche in which function is a direct consequence of intrinsic disorder. Gathering information on MR protein interactome has significant implications for understanding the molecular basis of the mechanisms responsible for the stability of tumor cell states. In this work, we focused on a subset of 128 MR proteins predicted from RNA-Seq profiles to be responsible for the Breast Invasive Carcinoma (BRCA) tumor homeostatic control across five distinct cancer subtypes and analyzed their disorder prevalence, functional importance, and potential roles in protein association networks. The disorder profile annotation was performed using the MobiDB-lite disorder meta-predictor. The proteins were classified according to the percentage of intrinsically disordered residues (PIDR) as highly ordered (PIDR < 10%), moderately disordered (10% ≤ PIDR < 30%), and highly disordered (PIDR ≥ 30%). We also evaluated target proteins using the CH-CDF plot, which is a combination of two binary disorder predictor methods: the charge-hydropathy plot (CH), that considers charge and hydrophobicity of amino acids, and the cumulative distribution function (CDF) plot, which is based on the distribution of per-residue disorder predictor scores. Disorder functional annotation was performed by mapping MoRFs and SLiMs using experimentally curated databases. The PrePPI database was used to predict interactivity of the BRCA MR proteins by constructing five cancer-specific protein-protein interaction (PPI) networks. Statistical significance of connectivity for the subtype interactomes was measured by the network-based distance method. Annotation of abundant/ housekeeping genes and network topology (hubs and bottlenecks) was introduced to correlate disorder, gene essentiality, and promiscuous binding activity. The result of this work is a comprehensive, functionally annotated inventory of the intrinsically disordered status of BRCA MR proteins. Our work revealed that the master regulator candidates are enriched in moderate (44%) and high (28%) intrinsic disorder and provide the groundwork for experimental studies that may uncover novel pathways associated with the aberrant protein activity that determine stable tumor states and predict IDPs as novel drug targets. Citation Format: Julia V. Castro, Evan O. Paull, Jose I. Garzon, Diana Murray, Andrea Califano, Barry Honig. Uncovering the disorder of breast invasive carcinoma homeostasis proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 285.