David Potter, MD, PhD

• Novel therapeutics for breast cancer

Regulation of calpain proteases and their roles in cytoskeletal remodeling; the roles of cytochrome P450 in breast cancer progression
Three enzymatic pathways of arachidonic acid metabolism, involving cyclooxygenases, lipoxygenases and epoxygenases, have been identified in mammalian cells, but only the first two have been mechanistically linked to human cancer. The HIV protease inhibitor ritonavir is a potent inhibitor of epoxygenases that arrests the growth of breast cancer xenografts, but its mechanism of action is unknown. Epoxygenases promote the production of epoxyeicosatrienoic acids (EET’s) that activate Akt kinase. Our studies seek to determine whether epoxygenases are cancer therapeutic targets. The hypothesis to be tested is that epoxygenase activation promotes breast cancer progression by promoting Akt phosphorylation and cancer cell survival. Based on our observations we are asking the following questions: What are the molecular mechanisms by which epoxygenases cause growth dysregulation in breast cancer? Do epoxygenases enhance the transforming activities of oncogenes in mammary carcinoma? Do epoxygenase pathways require Hsp90 activity for cancer cell survival? Targeted lipidomics will be used to assay EET regio- and stereoisomers. These studies will promote further development of epoxygenases as targets for breast cancer therapeutics.