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

Metastatic progression of epithelial cancers can be associated with epithelial-mesenchymal transition (EMT) including transcriptional inhibition of E-cadherin (CDH1) expression. Recently, EM plasticity (EMP) and E-cadherin–mediated, cluster-based metastasis and treatment resistance have become more appreciated. However, the mechanisms that maintain E-cadherin expression in this context are less understood. Through studies of inflammatory breast cancer (IBC) and a 3D tumor cell “emboli” culture paradigm, we discovered that cyclooxygenase 2 (COX-2; PTGS2), a target gene of C/EBPδ (CEBPD), or its metabolite prostaglandin E2 (PGE2) promotes protein stability of E-cadherin, β-catenin, and p120 catenin through inhibition of GSK3β. The COX-2 inhibitor celecoxib downregulated E-cadherin complex proteins and caused cell death. Coexpression of E-cadherin and COX-2 was seen in breast cancer tissues from patients with poor outcome and, along with inhibitory GSK3β phosphorylation, in patient-derived xenografts (PDX) including triple negative breast cancer (TNBC).Celecoxib alone decreased E-cadherin protein expression within xenograft tumors, though CDH1 mRNA levels increased, and reduced circulating tumor cell (CTC) clusters. In combination with paclitaxel, celecoxib attenuated or regressed lung metastases. This study has uncovered a mechanism by which metastatic breast cancer cells can maintain E-cadherin–mediated cell-to-cell adhesions and cell survival, suggesting that some patients with COX-2+/E-cadherin+ breast cancer may benefit from targeting of the PGE2 signaling pathway.

上皮性癌症的转移进展可能与上皮 - 间质转化（EMT）有关，包括E - 钙黏蛋白（CDH1）表达的转录抑制。最近，上皮间质可塑性（EMP）以及E - 钙黏蛋白介导的、基于细胞簇的转移和治疗抗性越来越受到关注。然而，在这种情况下维持E - 钙黏蛋白表达的机制却鲜为人知。通过对炎性乳腺癌（IBC）以及三维肿瘤细胞“栓子”培养模式的研究，我们发现环氧合酶2（COX - 2；PTGS2），一种C/EBPδ（CEBPD）的靶基因，或其代谢产物前列腺素E2（PGE2）通过抑制GSK3β促进E - 钙黏蛋白、β - 连环蛋白和p120连环蛋白的蛋白质稳定性。COX - 2抑制剂塞来昔布下调E - 钙黏蛋白复合蛋白并导致细胞死亡。在预后不良的乳腺癌患者的组织中观察到E - 钙黏蛋白和COX - 2共表达，并且在包括三阴性乳腺癌（TNBC）在内的患者来源的异种移植物（PDX）中，伴随着抑制性的GSK3β磷酸化。单独使用塞来昔布会降低异种移植物肿瘤内的E - 钙黏蛋白蛋白表达，尽管CDH1 mRNA水平升高，并且减少循环肿瘤细胞（CTC）簇。塞来昔布与紫杉醇联合使用时，可减轻或消退肺转移。这项研究揭示了一种转移性乳腺癌细胞能够维持E - 钙黏蛋白介导的细胞间黏附和细胞存活的机制，表明一些COX - 2⁺/E - 钙黏蛋白⁺乳腺癌患者可能受益于PGE2信号通路的靶向治疗。