The Paradox of E-Cadherin: Role in response to hypoxia in the tumor microenvironment and regulation of energy metabolism

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.

<em>Ex Vivo</em> Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics

“…Additional analysis of the viable IDC spheroids by immunofluorescence revealed a persistent or re-expression of the cell-cell adhesion molecule, E-cadherin (Figure 1C). This finding is consistent with persistent, over-expression of E-cadherin adding to the metastatic potential or metastatic efficiency as reflected in the highly malignant, lethal inflammatory breast cancer 12, 13 . Although interesting, this finding is beyond the scope of this paper.…”

Induction of entosis by epithelial cadherin expression

“…Entosis is another mechanism by which the expression of E-cadherin limits transformed growth by inducing cell death. However, many breast tumors including the most invasive ductal carcinomas and metastatic tumors retain E-cadherin expression, and E-cadherin may promote tumor progression by supporting cell survival, collective modes of invasion, or the outgrowth of metastatic tumors that may be promoted by an epithelial rather than mesenchymal phenotype [19,[33][34][35][36][37][38][39]. Like E-cadherin, P-cadherin is also expressed in some breast cancers and is a poor prognostic indicator [20].…”

Adhesion in Mammary Development

“…The function of E-cadherin in such tumors and validation of its potential role in promoting invasion remains a major open area for future research (Rodriguez et al, 2012). It is also important to distinguish whether E-cadherin’s role in cell migration is primarily through direct control of intercellular adhesion or instead through regulation of intracellular signaling networks (Chu, Boley, Moraes, Barsky, & Robertson, 2013). …”