Does E-cadherin-dependent adhesion inhibit integrin-activated MAP kinase phosphorylation

One of the important differences between malignant cells and non-malignant cells in cell culture is that non-malignant cells will proliferate until they contact adjacent cells and then are signaled to stop growing, called contact inhibition. Malignant cells continue to proliferate and frequently form multiple layers. Activation of the mitogen-activated protein (MAP) kinase pathway is an early event in signaling cell proliferation. In this thesis, I am testing the hypothesis that up-regulating E-cadherin expression in malignant breast cancer cells could inhibit integrin-dependent adhesion signals for MAP kinase pathway activation. In addition, down-regulation of E-cadherin expression in nonmalignant cells was tested to see if the cells would act more like malignant cells and activate MAP kinase pathway despite cell-cell contact inhibition. The observation that malignant cancer cells do not show cell-cell contact inhibition has been linked to the observation that they express reduced levels of E-cadherin compared to non-malignant cells. It was previously shown that integrin-dependent adhesion of non-malignant cells to fibronectin promoted MAP kinase activation at low cell density, but at high cell density MAP kinase activation was inhibited. In contrast, cancer cells are not capable of inhibiting integrin-dependent activation of MAP kinase. In malignant MDA-MB-23 1 cells, up-regulation of E-cadherin expression was tested to determine if this would make the cells act less malignant. The results of this study suggested that up-regulating E-cadherin expression was insufficient to convincingly promote less malignant behavior. However, non-malignant HSG cells which showed cell-cell contact inhibition of integrin-dependent MAP kinase phosphorylation were tested for the effects of down-regulating E-cadherin expression. The results of these studies indicate that E-cadherin expression contributes to cell-cell contact inhibition in HSG cells since cells with decreases levels of E-cadherin were able to activate MAP kinase even at high density. Our result should that down regulating E-cadherin expression in malignant and non-malignant cells increased the phosphorylation of MAP kinase pathway in high cell density. The goal of this study was to control tumor progression through modulating and restoring E-cadherin expression in malignant cells.