Abstract 1731: Functional genomics approach reveals distinct neo-morphic activities and co-driver mutations of different missense mutant TP53 that promote breast cancer heterogeneity and progression

Abstract

Abstract Phenotypic and molecular profiling of breast cancer demonstrates a high degree of heterogeneity in the breast tumors. TP53 tumor suppressor is mutated in 30% of all breast tumors and 80% of the basal-like subtype with numerous co-existing somatic mutations in other genes. We hypothesize that tumor heterogeneity is a result of combination of neo-morphic functions of specific TP53 driver mutations and functionally important but distinct co-mutations (or ‘co-drivers’) for each type of TP53 mutation. We thus ectopically expressed 10 most common missense p53 mutant proteins found in breast cancer patients in normal-like mammary epithelial cells and examined their phenotypes associated with various hallmarks of cancer. Supporting our hypothesis, a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell invasion and cell polarity across the 10 mutant cell lines were observed compared to those of WT p53 expressing cells. Integrated analysis of ChIP-seq and RNA-seq showed distinct promoter binding profiles of different p53 mutant proteins, implying that non-canonical transcriptional activity of mutant p53 proteins may contribute to the phenotypic heterogeneity in TP53-mutated tumor. Further, enrichment and model-based pathway analyses revealed the key biological pathways associated with invasion of cells expressing different p53 mutant proteins. As a proof-of-concept for screening co-drivers of mutant p53, when PTEN was deleted in non-invasive cells expressing p53-Y234C mutant using CRISPR-Cas9 system, an increase in cell invasion was observed. A genome-wide CRISPR library-based screen on p53-Y234C and p53-R273C cells identified completely different candidate co-driver mutations that promoted cell invasion. The top candidates included several known mutated genes in breast cancer patients harboring TP53 mutations and were associated with cytoskeletal and apoptosis resistance pathways. Overall, our combined approach of molecular profiling and functional genomics screens highlighted distinct sets of genes and co-driver mutations that can lead to heterogeneous phenotypes and promote aggressive behaviors of cells with different TP53 mutant backgrounds, which can guide development of novel targeted therapies. Citation Format: Anasuya Pal, Anasuya Pal. Functional genomics approach reveals distinct neo-morphic activities and co-driver mutations of different missense mutant TP53 that promote breast cancer heterogeneity and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1731.