Endonuclease-mediated DMA strand breaks interfere with replication, induce apoptotic DMA fragmentation and ultimately cell death. To the contrary, breast cancer progression is associated with decreased apoptosis, and an increased rate of DMA synthesis. This discrepancy could be explained by a deficiency of an endonuclease in poorly differentiated invasive breast cancer cells. However, the concept that an endonuclease deficiency may be essential for breast cancer progression has not been previously considered, and a relationship between an endonuclease and cancer progression has not been examined. We hypothesize that EndoG deficiency is essential for the progression of breast cancer by limiting apoptosis, allowing high rate of DMA synthesis, and that EndoG deficiency can be used as a new biomarker for human breast cancer progression. The purpose of this study is to determine whether EndoG deficiency is a common phenomenon in breast cancer progression, and whether it is mechanistically linked to the breast cancer dediffefentiation and increased invasiveness. If according to our expectation, EndoG will be shown to be the cause of breast cancer progression, it may be used in the future as a very reliable biomarker of breast cancer progression. Our strategy will be first to examine EndoG regulation as a function of differentiation and invasiveness of breast cancer cells in Specific Aim 1. The next specific aim will be focused on functional studies to determine the role of EndoG in dedifferentiation and invasiveness of breast cancer cells in vitro (Specific Aim 2).

R03CA114729

2005-09-30

2008-08-31