Oncotarget

Research Papers:

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

Khoi Chu, Kimberkey M. Boley, Ricardo Moraes, Sanford H. Barsky and Fredika M. Robertson _

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Oncotarget. 2012; 4:446-462. https://doi.org/10.18632/oncotarget.872

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Abstract

Khoi Chu1, Kimberley M. Boley1, Ricardo Moraes1, Sanford H Barsky2 and Fredika M. Robertson1

1 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX

2 Department of Pathology, The University of Nevada School of Medicine, Reno, NV

Correspondence:

Fredika M. Robertson, email:

Keywords: E-Cadherin, Inflammatory Breast Cancer, Mesenchymal-Epithelial Transition (MET), Hypoxia-inducible 1α transcription factor (HIF-1α), Metabolism, Glycolysis.

Received: March 15, 2013 Accepted: March 21, 2013 Published: March 21, 2013

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.


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