Abstract 551: Discovering the co-drivers of mutant TP53 that promote breast cancer progression

Abstract

Abstract Breast cancer is a heterogeneous disease and has different subtypes. Genetically 30% of all breast tumors and 80% of basal-like breast tumors harbor mutations in TP53 and numerous somatic mutations in other genes. This molecular heterogeneity has posed a challenge in developing effective therapeutic regimens and targeted therapies. Different TP53 missense mutations co-exist with other mutations in tumors and we hypothesize that tumor heterogeneity results from combinatorial effects of neo-morphic functions of specific TP53 driver mutations and a distinct subset of functionally important co-mutations (or ‘co-drivers'). We ectopically expressed the ten most prevalent missense TP53 mutants found in breast cancer tumors in non-transformed mammary epithelial cells and examined their phenotypes associated with the hallmarks of cancer. The results showed wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell invasion and cell polarity. As a proof of concept for the ‘co-driver', we knocked-out PTEN in a non-invasive TP53 Y234C mutant using the CRISPR system and observed increased cell invasion. A subsequent genome-wide CRISPR library-based screen on non-invasive TP53 Y234C expressing cells identified co-driver candidates that were highly enriched in the invasive population of Y234C cells. The top candidates included several known mutated genes in breast cancer patients with TP53 mutations, and were associated with signaling and cytoskeletal pathways that play crucial role in regulating cell invasion. These results demonstrate that this approach can pinpoint the key loss-of-function mutations in clinically important TP53 mutant backgrounds that can promote cancer-like behavior, and identify the combinations of ‘TP53 mutant and co-driver pathways' that can be targeted by specific inhibitors. Citation Format: Anasuya Pal, Jin Park, Joshua LaBaer. Discovering the co-drivers of mutant TP53 that promote breast cancer progression [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 551.