Abstract
E-Cadherin is a cell:cell adhesion molecule critical for appropriate embryonic and mammary development. In cancer, E-Cadherin has been primarily viewed as being lost during the process of epithelial-mesenchymal transition (EMT), which occurs with a switch from E-Cadherin expression to a gain of N-Cadherin and other mesenchymal markers. EMT has been shown to play a role in the metastatic process while the reverse process, mesenchymal-epithelial transition (MET), is important for metastatic colonization. Here we report an unexpected role of E-Cadherin in regulating tumorigenicity and hypoxia responses of breast tumors in vivo. Reduced expression of E-Cadherin led to a dramatic reduction of the in vivo growth capability of SUM149, Mary-X and 4T1 tumor cells. Furthermore, over-expression of ZEB1, a known transcriptional repressor of E-Cadherin, led to reduced in vivo growth of SUM149 tumors. Gene set enrichment analysis identified the loss of hypoxia response genes as a major mechanism in mediating the lack of in vivo growth of SUM149 cells that lacked E-Cadherin or over-expressed ZEB1. The in vivo growth defect of SUM149 E-Cadherin knockdown tumors was rescued by the hypoxia-inducible 1α transcription factor (HIF-1α). Given the importance of HIF-1α in cellular metabolism, we observed reduced glycolytic capacity in SUM149 and 4T1 cells that had E-Cadherin knocked down. Our observations shed light on the complex functions of E-Cadherin in retention of an epithelial phenotype and as a mediator of survival of aggressive breast cancer under hypoxic conditions in vivo. Furthermore, we find that patients with basal subtype breast cancer and high E-Cadherin expression in their tumors had a poor clinical outcome. Our data suggests a novel function for E-Cadherin as a bona fide signaling molecule required for the in vivo growth of aggressive breast cancer tumor cells, that retain E-Cadherin expression, in mediating their metabolic function.
Highlights
E-Cadherin is a glycoprotein involved in cell:cell adhesion and is essential for appropriate embryonic and mammary development [1,2,3]
The induction of epithelial mesenchymal transition (EMT) and loss of E-Cadherin is believed to be an essential primary step in the initiation of metastasis, it is well accepted that tumors are quite heterogeneous and loss of E-Cadherin is not always associated with increased invasive behavior [15]
The plasticity of the linked reversible processes of EMT and mesenchymal-epithelial transition (MET) suggests that cancer cells retain a control in the degree of cellular re-programming and may select EMT features such as invasion while maintaining epithelial features such as E-Cadherin expression
Summary
E-Cadherin is a glycoprotein involved in cell:cell adhesion and is essential for appropriate embryonic and mammary development [1,2,3]. While the current paradigm of the acquisition of an invasive phenotype has been associated with a loss of E-Cadherin during the process of the epithelial mesenchymal transition (EMT), studies in a number of carcinoma types show that tumors are quite heterogeneous and loss of E-Cadherin is not always associated with increased invasive behavior. Maintenance of E-Cadherin expression in highly metastatic cell lines has been described in a number of pre-clinical models of metastasis of breast (4T1), prostate (DU145), and bladder (TSU-Pr1) cancers [6,7,8]. This has recently been referred to as “the dark side of E-Cadherin” [9, 10]. IBC represents the prototype breast cancer with prominent MET similar to ovarian cancer
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