Research Abstract

A major research focus in the laboratory is the regulation of carcinoma cell migration and invasion, with emphasis on the signaling pathways which impact this phenotype. Work in our laboratory has focused on transcription factors of the NFAT (Nuclear Factor of Activated T cells) family. We have found that NFATs are expressed and functionally active in cancer cells, and that NFAT transcriptional activity is required for promoting carcinoma invasion (Jauliac, NCB 2002). The significance of these studies is that they afford insight into a gene, NFAT, not previously known as being important for human carcinoma invasion and metastasis, and may thus provide a novel approach for targeted drug design for anti-tumor therapies. More recent studies have focused on the role of the Akt proto-oncogene in modulating breast cancer progression. We have discovered that Akt1 is breast cancer cell motility and invasion suppressor, a surprising finding considering that the PI 3-K and Akt pathway is clearly implicated in tumor progression (Yoeli-Lerner, Mol. Cell 2005). The significance of these findings is that small molecule inhibitors of Akt, currently being developed by many pharmaceutical companies, may actually enhance tumor invasion and metastasis. We have also discovered that a secreted variant of ADAM9, termed ADAM9-S, a member of the A Disintegrin And Metalloprotease family of matrix metalloproteases, is expressed and secreted by stromal cells in the tumor microenvironment, and promotes tumor invasion (Mazzocca, Can. Res. 2005). The current focus is to gain additional insight into the role of NFAT, Akt and ADAM9-S in invasion and migration, as well as genome-wide screens for genes induced by these pathways in carcinoma cells and the use of animal modes of invasion and metastasis to determine the importance of these proteins in the progression of the disease.

Another major research focus in the laboratory is the function of the serine/threonine kinase PKD (protein kinase D) in cancer cell biology. Our studies have shown that PKD is critical for the activation of the transcription factor NF-kB, leading to increased cellular survival in response to mitochondrial oxidative stress (Storz et al, MCB 2005). The significance of these results is that they describe a signaling pathway which cells use to increase their survival capacity under conditions of oxidative stress. ROS have been implicated in numerous human pathologies, including cancer, inflammation, Parkinson’s disease, and are also believed to be major causative factors in human aging. Future goals include analysis of the mechanisms by which PKD regulates NF-kB and in particular the discovery of specific PKD substrates and how they relay signaling pathways. Thus, we have an active and long-term interest in kinase signaling and how it impacts downstream signaling pathways leading to cell growth, survival and motility.