Breast cancer is a very heterogeneous disease. Many pathological alterations contribute to breast cancer development. Some of these are fundamental changes that initiate the cancer formation or accelerate its progression. To effectively cure breast cancer, we need a thorough knowledge of these fundamental changes so that we can take advantage of their weaknesses to specifically kill breast cancer cells but not normal tissue. One of the fundamental alterations in breast cancer is loss of cell cycle control.
Our bodies counter tremendous DNA damaging stresses from the environment, such as ?-irradiation, UV, carcinogens, or even from our daily metabolic processes. If DNA damage occurs without being repaired in the genes controlling cell growth or mortality, cells will acquire altered growth properties and become transformed, and cancer will eventually develop. Fortunately, our bodies have natural defense mechanisms to keep the damaged cells in check so that the damaged genes can be repaired. We call this defensive machinery the ¿checkpoint¿ mechanism. In this proposal, we plan to study Chk2, one of the central components of this machinery, for its role in managing our defensive system to repair damaged DNA and to suppress cellular transformation. It is believed that loss of checkpoint function of Chk2 may contribute to breast cancer formation or progression. However, how and to what extent it contributes to breast cancer development is still unknown. We believe that the role of Chk2 in tumor suppression will not become clear until its biological functions and regulatory pathways can be identified.
In our studies, we will first generate the human epithelial cells that have no Chk2 expression (i.e., Chk2 null cells) for use as a model. By studying the responses to DNA damaging agents and the transformation potential in Chk2 null cells, we can determine the significance of Chk2 functions in managing checkpoints and in suppressing transformation. Next, we will ask how Chk2 executes those functions. We plan to systematically identify Chk2 substrates and its associated proteins so that we can discover the entire network connecting to Chk2. The knowledge that we will obtain from cultured cells will also be confirmed clinically by studying breast cancer specimens. We believe that the mechanisms and targets discovered in our studies will be critical for developing more effective approaches in breast cancer therapy in future.