Abstract 2429: Generation of a transcriptome of oncogenic mutant p53 in triple-negative breast cancer

Abstract

Abstract The purpose of this study was to generate a transcriptional profile specific for mutant p53 in triple-negative breast cancer (TNBC), representing potential novel therapeutic targets. The highly heterogeneous TNBC tumor subgroup is established as having a poor clinical outcome. There are currently no targeted therapies for women with TNBC; consequently, there is an unmet clinical need to identify targetable pathways. Approximately 75% of these tumors are known to harbour a mutation in Tp53 (mutp53). Chromatin Immunoprecipitation Sequencing (ChIP-Seq) for mutp53 and ETS-1 (a known mutp53 interactor) was carried out using the D0-1 (sc-126) and sc-20 antibodies respectively, in the MDA-MB-468 TNBC cell line. The aim of these ChIP-seq experiments was to identify sites bound by endogenous R273H mutp53 and ETS-1 and to confirm that target genes were co-regulated. We identified 282 novel mutp53 specific genomic binding sites and 37 mutant p53 and ETS1 shared binding sites. In-house data analysis and peak calling generated a list of potential transcriptionally co-regulated genes adjacent to these genomic sites. PDGFβ, TRIB3, BTRC, TNFSF18 & PI3 were successfully validated as being transcriptionally regulated by R273H mutp53 and not wild-type p53 (as shown by MCF7 ChIP-seq comparisons). A number of these genes are known to be aberrantly expressed in TNBC patient tumors and harbor interesting immune biology, providing potential opportunities for novel therapeutic strategies. In addition, DNA damaging chemotherapy-resistant MDA-MB-468 derivatives express elevated levels of mutp53 protein and altered expression of our validated transcriptional targets, suggesting that they may also have roles in promoting resistance to current chemotherapy treatments, downstream of mutp53. In conclusion, we have identified a cohort of ‘mutp53 specific’ transcriptional targets which may have roles in modulating immune responses to TNBCs, driving resistance to current chemotherapies and could provide opportunities for the development of novel treatments for TNBCs. Citation Format: Rebecca E. Steele, Simon S. McDade, Paul B. Mullan. Generation of a transcriptome of oncogenic mutant p53 in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2429. doi:10.1158/1538-7445.AM2017-2429