Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer

Balamurugan, K.; Sehareen, S.; Sharan, S.; Krishnamurthy, S.; Tang, W.; McKennett, L.; Padmanaba, V.; Czarra, K. T.; Ewald, A. J.; Ambs, S.; Ueno, N. T.; Poria, D. K.; Sterneck, E.

doi:10.1101/2022.01.18.476813

bioRxiv · 10.1101/2022.01.18.476813

Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer

Balamurugan, K.·Sehareen, S.·Sharan, S.·Krishnamurthy, S.·Tang, W.·McKennett, L.·Padmanaba, V.·Czarra, K. T.·Ewald, A. J.·Ambs, S.·Ueno, N. T.·Poria, D. K.·Sterneck, E.

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Abstract

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/EBP{delta}, or its metabolite PGE2 in promoting protein stability of E-cadherin, {beta}-catenin and p120 catenin through inhibition of GSK3{beta}, 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 GSK3{beta} 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.

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Balamurugan, K., Sehareen, S., Sharan, S., Krishnamurthy, S., Tang, W., McKennett, L., Padmanaba, V., Czarra, K. T., Ewald, A. J., Ambs, S., Ueno, N. T., Poria, D. K., Sterneck, E.. 2022-01-21. Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. https://doi.org/10.1101/2022.01.18.476813

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