PT - JOURNAL ARTICLE AU - Kuppusamy Balamurugan AU - Saadiya Sehareen AU - Shikha Sharan AU - Savitri Krishnamurthy AU - Wei Tang AU - Lois McKennett AU - Veena Padmanaban AU - Kelli Czarra AU - Andrew J. Ewald AU - Naoto T. Ueno AU - Stefan Ambs AU - Dipak K. Poria AU - Esta Sterneck TI - Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer AID - 10.1101/2022.01.18.476813 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.01.18.476813 4099 - http://biorxiv.org/content/early/2022/01/21/2022.01.18.476813.short 4100 - http://biorxiv.org/content/early/2022/01/21/2022.01.18.476813.full AB - Metastatic progression and treatment-resistance of breast cancer has been associated with epithelial-mesenchymal-transition including downregulation of E-cadherin (CDH1) expression, which can be initiated by inflammatory mediators such as COX-2. Recently, E-cadherin-mediated, cluster-based metastasis and treatment resistance has become more appreciated, though the mechanisms that maintain E-cadherin expression in this context are unknown. Through studies of inflammatory breast cancer and an in vitro tumor cell emboli culture paradigm, we identified a role for COX-2, a target gene of C/EBPδ, or its metabolite PGE2 in promoting protein stability of E-cadherin, β-catenin and p120 catenin through inhibition of GSK3β, without affecting CDH1 mRNA. The COX-2 inhibitor celecoxib downregulated E-cadherin complex proteins and caused cell death. Co-expression of E-cadherin and COX-2 was seen in breast cancer patients with poor outcome and, along with inhibitory GSK3β phosphorylation, in patient-derived xenografts of triple negative breast cancer. Celecoxib alone decreased E-cadherin protein expression within xenograft tumors, reduced circulating tumor cells and clusters, and in combination with paclitaxel attenuated or regressed lung metastases. This study uncovered a mechanism by which metastatic breast cancer cells can maintain E-cadherin-mediated cell-cell adhesions and cell survival, suggesting that patients with COX-2+/E-cadherin+ breast cancer may benefit from targeting of the PGE2 signaling pathway.Competing Interest StatementThe authors have declared no competing interest.