The paradox of E-cadherin: role in response to hypoxia in the tumor microenvironment and regulation of energy metabolism

Oncotarget. 2013 Mar;4(3):446-62. doi: 10.18632/oncotarget.872.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Energy Metabolism / genetics*
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Profiling
  • Glycolysis / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • MCF-7 Cells
  • Metabolomics
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • RNA Interference
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Burden / genetics
  • Tumor Microenvironment / genetics*
  • Xenograft Model Antitumor Assays / methods
  • Zinc Finger E-box-Binding Homeobox 1


  • Cadherins
  • HIF1A protein, human
  • Homeodomain Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1