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The Desmoid Tumor Research Foundation

July 2020

Beta-catenin S45F mutation results in apoptotic resistance

Author Information

Braggio D(1,2), Zewdu A(1,2), Londhe P(3), Yu P(4), Lopez G(1,2), Batte K(1,2), Koller D(1,2), Casal de Faria FC(1,2), Casadei L(1,2), Strohecker AM(2,5,6), Lev D(7,8), Pollock RE(1,2).

(1)Program in Translational Therapeutics, The James Comprehensive Cancer Center, The Ohio State Univ, Columbus, OH. (2)Dept of Surgery, The Ohio State Univ, Columbus, OH. (3)Millipore Sigma, Burlington, MA. (4)Medical Student Research Program, The Ohio State Univ, Columbus, OH. (5)Program in Molecular Biology and Cancer Genetics, The James Comprehensive Cancer Center, The Ohio State Univ, Columbus, OH. (6)Dept of Cancer Biology and Genetics, College of Medicine, The Ohio State Univ, Columbus, OH. (7)Surgery B, Sheba Medical Center, Tel Aviv, Israel. (8)Tel Aviv Univ, Tel Aviv, Israel.

Publication

Oncogene

Summary

Wnt/beta-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 beta-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of beta-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in beta-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 beta-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 beta-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/beta-catenin signaling induced by this mutation.

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