Three enzymatic pathways of arachidonic acid metabolism, involving cyclooxygenases, lipoxygenases, and cytochrome P450 epoxygenases, have been identified in mammalian cells, but only the first two have been 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. This project seeks 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.
The specific aims are: 1. To establish the molecular mechanisms by which epoxygenases cause growth dysregulation in breast cancer, 2. To establish that epoxygenases enhance the oncogenic potential of the Ha-ras oncogene in mammary carcinoma. 3. To establish that the epoxygenase pathway activates and requires Hsp90 for cancer cell survival. Targeted lipidomics using the method of electron capture APCI-MS/MS will be used to profile EET regio- and stereoisomers. A bacterial epoxygenase will be tested for cooperation with activated Ha-ras in breast cancer progression. These studies will promote further development of epoxygenases as targets for breast cancer therapeutics. ? ?
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