Biomarkers and treatment options for advanced and recurring illnesses are scarce. Although the mechanism of action of bevacizumab, an anti-angiogenesis medication, is uncertain, endometrial malignancies (ECs) with CTNNB1 exon 3 mutations appear to have a preferred response to this therapy. The goal of researchers was to determine what mechanisms allow endometrial malignancies to respond to bevacizumab. They compared TCGA RNA expression with CPTAC protein expression to determine potential β-catenin overactivity targets. 

They subsequently overexpressed β-catenin in EC cells both transiently and permanently to verify the predictions of their computational model. Using CTNNB1 silencing in mutant cell lines as a proof-of-concept experiment, they were able to show that the mutation had a functional effect. To examine microvessel density, they implanted transduced cells into xenograft models. There was a significant correlation between CTNNB1 mutations and elevated levels of β-catenin and matrix metalloproteinase 7 (MMP7) in ECs (P < 0.001), but not VEGF-A. In contrast to what was expected, overexpressing β-catenin in EC cells did not result in a rise in VEGF-A levels but did enhance MMP7 expression and secretion (P < 0.03). In CTNNB1-mutated cells, silencing CTNNB1 reduced MMP7 gene expression in EC (P < 0.0001). The density of microvessels was not increased. 

These findings explain the mechanism underlying the bevacizumab response observed in CTNNB1-mutant ECs in GOG-86P. They postulated that MMP7, once overexpressed and released, digests VEGFR-1, releasing VEGF-A and thereby boosting its availability. These processes may promote the development of leaky blood vessels, which aids tumor growth, metastasis, and immunological suppression. Given the specificity of this pathway for EC, it is important to conduct additional clinical trials investigating this biomarker in relation to treatment.