β-catenin S45F mutation results in apoptotic resistance

Danielle Braggio*, Abeba Zewdu, Priya Londhe, Peter Yu, Gonzalo Lopez, Kara Batte, David Koller, Fernanda Costas Casal de Faria, Lucia Casadei, Anne M. Strohecker, Dina Lev, Raphael E. Pollock*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.

Original languageEnglish
Pages (from-to)5589-5600
Number of pages12
JournalOncogene
Volume39
Issue number34
DOIs
StatePublished - 20 Aug 2020

Funding

FundersFunder number
National Institutes of Health1K22CA187931
National Cancer InstituteU54CA168512, P30CA016058
Desmoid Tumor Research Foundation
Center for Strategic Scientific Initiatives, National Cancer Institute

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