Relating copper homeostasis to breast cancer drug sensitivity and invasiveness

Metastasis of epithelia-derived tumors, including breast cancer, requires tightly attached cells to move away from their neighbors, enter circulation, survive, exit circulation and re-initiate tumor growth in a new environment. One of the mechanisms by which epithelial cells can accomplish this is by using the epithelial-mesenchymal transition (EMT), a developmentally conserved biological process. Many signaling pathways and molecules play essential roles in EMT. Copper is required for numerous biological functions, and may play an essential role in EMT. To test this, we manipulated expression of a copper transport protein in breast cancer cells and measured effects on EMT status as well as sensitivity to copper chelating agents. Unexpectedly no impact on EMT and only modest impacts on drug sensitivity were observed. Nevertheless, using a hypoxia mimic to induce EMT, we found that TEPA, a copper chelator, mitigates associated morphological changes and migratory abilities. Based on these data, we conclude that copper transporters are not essential for maintaining the epithelial phenotype, yet copper is required for hypoxia mimic-induced EMT.