Control of apoptosis in breast by growth factors and extracellular matrix: targets for therapeutic intervention

Cell survival is adhesion-dependent in normal breast epithelium. Survival requires the integrin class of extracellular matrix (ECM) receptors. We have demonstrated that specific ECM such as basement membrane promote cell survival, whereas others, including collagen I, do not. Basement membrane proteins are largely absent around invasive breast cancer cells. Thus, cancer cells have lost their specific ECM-dependency, presumably due to inappropriate activation of adhesion-regulated survival enzymes. Such enzymes represent potential targets for cancer intervention, particularly where there is sufficient redundancy of signalling on basement membrane to provide reduced or no dependency in normal cells. We have shown that pp125FAK mediates integrin survival signals in breast epithelia, and phosphatidylinositol 3-kinase overcomes apoptosis induced by dominant negative pp125FAK. Signals downstream of pp125FAK regulate apoptosis through a control on the activity of the proapoptotic protein Bax.

Signal transduction through growth factor receptors can be regulated by adhesive interactions via integrins. We have discovered that pharmacological inhibition of epidermal growth factor receptor signalling strongly induces apoptosis in breast epithelia. The mechanism of apoptosis induction appears not to be through Bax activation, but rather through dephosphorylation of the proapoptotic protein Bad.

Thus, different classes of potent survival regulators (ie adhesion and soluble factors) determine apoptotic cell fate within the same cells through independent control of different mitochondrial acting proapoptotic proteins. Our results broaden the scope for future strategies of cancer intervention.