26S proteasome is conserved, therapeutically relevant mediator of mutant p53 gain-of-function in cancer

ABSTRACT: Mutant p53 proteins, resulting form frequent TP53 tumor suppressor missense mutations, possess gain-of-function activities and are among the most widespread and robust oncoproteins in human tumors. They are potentially important but understudied therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects, from effects specific to different mutant variants and cell backgrounds. Here we identify 26S proteasome machinery as the common downstream effector controlled by mutant p53s in Triple Negative Breast Cancer (TNBC - aggressive carcinomas with TP53 as the most frequently mutated locus) and conserved in other human cancers. We have identified this pathway using a combination of single-model, multi-method vertical analysis (whole cell proteome, RNA sequencing an ChIP sequencing) and multi-cell line, horizontal analysis of transcriptiomes. We found that different missense mutant p53s regardless of the cell background transcriptionaly activate whole 26S proteasome machinery. Proteasome activity is significantly increased in p53 mutant versus wild-type or knockdown/null status - in cellular and mouse models as well as in human breast tumors. Increased proteasome activity leads to inhibition of tumor suppressive pathways. The control of mutant p53 over proteasome transcription and activity results in the increased resistance to proteasome inhibitors. By combining the mutant p53 targeting agents and proteasome inhibitor we were able to overcome the “bounce-back” proteasome inhibitor resistance mechanism in mutant p53 bearing TNBC cells and xenografts in vivo.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Mario Oroshi  

LAB HEAD: Jacek Wisniewski

PROVIDER: PXD001673 | Pride | 2016-05-03

REPOSITORIES: Pride