Elucidating the role of autophagy genes in cell death and epithelial cell cancer development

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Apoptosis has been studied in the context of cancer and cancer treatment for many years. However, it has recently become evident that autophagy also plays an important role in cell death and survival outside of the realm of nutrient deprivation and is critically important in tumor development and, perhaps, the response to cancer treatment. Our lab has found that normal, primary breast or prostate epithelial cells but not transformed cells can be killed by a Fas Associated Death Domain protein (FADD-DD)-dependent mechanism that involves autophagy as well as apoptosis. This implies that during transformation, epithelial cells developed a specific defect in the autophagic mechanism or in the connection between the apoptotic and autophagic mechanisms. Here, we show that disruption of this pathway occurs without affecting other cell death mechanisms at an early stage in the transformation process. We also determine the role of these mechanisms in epithelial transformation and the response to cancer therapy using short interfering RNA (siRNA) against autophagic genes, such as Beclin-1 (Atg6) and analysis of the interaction of the FADD protein with autophagy regulators.