DHPS-dependent hypusination of eIF5A1/2 is necessary for TGF?/fibronectin-induced breast cancer metastasis and associates with prognostically unfavorable genomic alterations in TP53.

ABSTRACT: Metastasis is the leading cause of mortality in patients with solid tumors. In this regard, we previously reported that Pseudopodium-Enriched Atypical Kinase One (PEAK1) is necessary for non-canonical Transforming Growth Factor ? (TGF?) signaling and TGF?/fibronectin-induced metastasis. Here, we demonstrate that inhibition of DHPS-dependent eIF5A1/2 hypusination blocks PEAK1 and E-Cadherin expression, breast cancer cell viability and TGF?/fibronectin-induced PEAK1-dependent breast cancer metastasis. Interestingly, TGF? stimulation of high-grade metastatic breast cancer cells increases and sustains eIF5A1/2 hypusination. We used a suite of bioinformatics platforms to search biochemical/functional interactions and clinical databases for additional control points in eIF5A1/2 and PEAK1-Epithelial to Mesenchymal Transition (EPE) pathways. This effort revealed that interacting EPE genes were enriched for TP53 transcriptional targets and were commonly co-amplified in breast cancer patients harboring inactivating TP53 mutations. Taken together, these results suggest that combinatorial therapies targeting DHPS and protein activities elevated in TP53-mutant breast cancers may reduce systemic tumor burden and improve patient outcomes.

SUBMITTER: Guth R 

PROVIDER: S-EPMC6801012 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature