Mechanisms of mutant β-catenin in endometrial cancer progression

Abstract

Endometrial carcinoma (EC) is the most diagnosed gynecological malignancy in Western countries. Both incidence and mortality rates of EC have steadily risen in recent years. Despite generally favorable prognoses for patients with the endometrioid type of EC, a subset of patients has been identified with decreased progression-free survival. Patients in this group are distinguished from other endometrioid EC patients by the presence of exon 3 hotspot mutations in CTNNB1, the gene encoding for the β-catenin protein. β-catenin is an evolutionarily conserved protein with critical functions in both adherens junctions and Wnt-signaling. The exact mechanism by which exon 3 CTNNB1 mutations drive EC progression is not well understood. Further, the potential contribution of mutant β-catenin to adherens junctions' integrity is not known. Additionally, the magnitude of worsened progression-free survival in patients with CTNNB1 mutations is context dependent, and therefore the importance of this subset of patients can be obscured by improper categorization. This review will examine the history and functions of β-catenin, how these functions may change and drive EC progression in CTNNB1 mutant patients, and the importance of this patient group in the broader context of the disease.

Keywords: Wnt-signaling; cell adhesion; endometrial cancer; tumor progression; β-catenin.

Figure 1

Schematic overview of canonical Wnt signaling. In the absence of a Wnt ligand, cytoplasmic β-catenin is phosphorylated in a multi-protein destruction complex comprised of scaffolding proteins Axin and APC and kinases GSK3β and CK1. Phosphorylation by the destruction complexes induces poly-ubiquitination of β-catenin and subsequent degradation by the proteasome. Upon Wnt ligand binding to the Frizzled receptor and LRP5/6 co-receptor, proteins in the destruction complex are recruited to the cell membrane, rendering the complex inoperative. Cytoplasmic β-catenin can now escape degradation and translocate to the nucleus, where it binds the TCF/LEF family of transcription factors and initiates target gene transcription.

Figure 2

β-catenin protein domains and primary binding partners. β-catenin is comprised of an approximately 150-amino-acid N-terminal domain, a 525-amino acid central Armadillo domain containing 12 Arm repeats, and an approximately 100-amino acid C-terminal domain. The N-terminus is the site of GSK3β and CK1 phosphorylation, as well as partial α-catenin binding. The Armadillo domain contains overlapping binding sites for α-catenin, E-cadherin, Axin, APC, and the TCF/LEF transcription factors.

Figure 3

Most commonly mutated β-catenin amino acid residues occurring in endometrial cancer. All mutations occur in exon 3, found within the N-terminus, blocking GSK3β or CK1 phosphorylation sites—S33, S37, T41, S45—or adjacent residues—D32, G34, and I35.

Figure 4

Proposed mechanism of exon 3 CTNNB1 mutations in endometrial cancer. Mutant β-catenin can escape degradation in the cytoplasm and translocate to the nucleus independent of Wnt-signaling. One mechanism by which mutant β-catenin may drive endometrial cancer is by inducing transcription of E-cadherin negative regulators or EMT genes. β-catenin mutations occur relatively early in endometrial cancer progression, whereas loss of E-cadherin occurs later in disease progression. Therefore, mutations to β-catenin may indirectly contribute to E-cadherin loss and EMT progression.