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The role of CTNNB1 mutations and matrix metalloproteinases (MMPs) in anti-angiogenesis treatment of endometrial carcinoma

Published:September 20, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.09.013

      Highlights

      • CTNNB1 mutated tumors treated with bevacizumab are associated with improved outcomes without identified mechanism.
      • CTNNB1 mutations appear to increase expression of MMP7 without directly increasing VEGF-A abundance.
      • CTNNB1 mutations may increase available VEGF-A in endometrial cancers via an MMP7-related mechanism.

      Abstract

      Objective

      Treatment options and associated biomarkers for advanced and recurrent disease are limited. Endometrial cancers (ECs) with CTNNB1 exon 3 mutations appear to have preferential response to bevacizumab, an anti-angiogenesis treatment, though the mechanism of action is unknown. We aim to identify mediators of bevacizumab-responsive endometrial cancers.

      Methods

      We analyzed RNA expression from TCGA and protein expression from CPTAC to identify likely targets for β-catenin overactivity. We then transiently and stably overexpressed β-catenin in EC cells to confirm the results suggested by our in silico analysis. We performed corroborative experiments by silencing CTNNB1 in mutated cell lines to demonstrate functional specificity. We implanted transduced cells into xenograft models to study microvessel density.

      Results

      CTNNB1-mutated ECs were associated with increased β-catenin and MMP7 protein abundance (P < 0.001), but not VEGF-A protein abundance. Overexpressing β-catenin in EC cells did not increase VEGF-A abundance but did increase expression and secretion of MMP7 (P < 0.03). Silencing CTNNB1 in CTNNB1-mutated cells decreased MMP7 gene expression in EC (P < 0.0001). Microvessel density was not increased.

      Conclusions

      These data provide a mechanistic understanding for bevacizumab-response in CTNNB1-mutated ECs demonstrated in GOG-86P. We hypothesize that overexpressed and secreted MMP7 potentially digests VEGFR-1, releasing VEGF-A, and increasing its availability. These activities may drive the formation of permeable vessels, which contributes to tumor progression, metastasis, and immune suppression. This mechanism is unique to EC and advocates for further clinical trials evaluating this treatment-related biomarker.

      Keywords

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