A major research focus in the laboratory is the regulation of carcinoma cell invasive migration, with emphasis on the signaling pathways which impact this phenotype.  Work in our laboratory has focused on transcription factors of the NFAT 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. 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. We are currently evaluating the importance of NFAT activity in breast cancer progression in vivo, as well as deciphering the transcriptional targets of NFAT in breast cancer cells.

We are also investigating the mechanisms by which the PI 3-kinase and Akt signaling pathway regulates breast cancer progression. Genes in the the PI 3-K pathway harbor some of the most frequent genetic lesions   in breast cancer. Our studies have focused on the role of the Akt kinase 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. Conversely, the Akt2 isoforms is an enhancer of invasive migration and metastatic dissemination. 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 are currently investigating the mechanisms by which Akt isoforms control invasive migration in vitro and in vivo, as well as conducting phospho-proteomic screens for novel Akt substrates, and evaluating the role of the related SGK kinase in breast cancer progression.

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. The current focus is to gain additional insight into the role of ADAM9-S and ADAM9-L 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.  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. Current goals include analysis of the mechanisms by which PKD promotes downstream signaling through identification of novel PKD substrates, as well as investigating the role of PKD isoforms in cancer progression.