Abstract 2917: The role of Methionine sulfoxide reductase A in metastasis of breast cancer.

The role of oxidative stress in several human diseases is very well established, but the effect of oxidative stress on cancer cells, especially resulting from mitochondrial dysfunction, appears to be quite complex. Warburg first showed that cancer cells have a defect in mitochondrial respiration which explains why these cells have a greater dependency on glycolysis for energy production than normal cells, even in the presence of adequate oxygen. Cancer cells have been reported to be more sensitive to reactive oxygen species (ROS) and are known to have lower levels of several antioxidant enzymes, which are thought to function as tumor suppressors. In support of this are recent findings that indicate increased levels of ROS make cancer cells more aggressive and promote metastasis. However, in contrast there are other studies that indicate elevated levels of antioxidant enzymes drive tumor cells to metastasize and also prolong tumor cell survival. Our goal is to clarify the role of oxidative stress and ROS on cancer cell viability and aggressiveness. The focus will be on an important protein repair and catalytic antioxidant enzyme system, methionine sulfoxide reductase (Msr). The Msr system in mammalian cells (comprised of MsrA, MsrB1, MsrB2, MsrB3) reduces the oxidized methionine residues (Met(O)) in proteins back to methionine. Furthermore, the Msr system plays an important role in scavenging ROS by permitting methionine residues in proteins to function as catalytic antioxidants. MsrA has been studied in most detail. This enzyme plays an important role in protection against increased oxidative stress in a variety of organisms and can affect the life span of yeast and animals. The objective of our study was to determine whether the expression of MsrA is altered during tumor progression and to identify the molecular targets that regulate MsrA. Our preliminary data show that MsrA is downregulated in several types of breast cancer. We have used two lines of human mammary epithelial 21T series that represent different stages of tumor progression from a single patient and compared with metastatic human breast cancer cell line MDA-MB-231. Our data indicates that non-metastatic 21PT has higher protein levels of MsrA compared to both metastatic 21MT-1 and MDA-MB-231 cell lines as evidenced by western blots. MsrA protein levels of nonmetastatic 21PT are much lower than normal epithelial cells. Levels of MsrA activity were higher in nonmetastatic 21PT than metastatic 21MT-1 as determined by enzymatic activity assays. Enzyme activity of MsrA is nearly two fold higher in nonmetastatic 21PT than the MsrA levels in metastatic MDA-MB-231 cells. Our preliminary results also indicate upregulation of oncogenic (c-Myc) protein levels in metastatic lines suggesting an inverse correlation with MsrA. It is therefore likely that MsrA may be an important antioxidant enzyme in breast cancer cells whose regulation drives tumor progression. Citation Format: Shailaja Kesaraju, Xiaoping Wu, Diane Baronas-Lowell, Herbert Weissbach. The role of Methionine sulfoxide reductase A in metastasis of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2917. doi:10.1158/1538-7445.AM2013-2917