Arachidonate Metabolism in Breast Cancer Cultures: Identification of Antagonist/Agonist for Possible Intervention Strategies.

Abstract : There has been increasing evidence that high intake of dietary fats and obesity, in general, correlate with increased risk 0 breast cancer. The breast, as an apocrinegland shroudedin fat pads, may possess special regulatory mechanisms to protect the epithelial cells from stimulation in the rich mileu of the surroundings. Our hypothesis suggests that loss of protective mechanisms in breast tissue leaves breast epithelial cells vulnerable to unregulated stimulation. Our studies have address regulatory mechanisms in production of bioactive lipids. We have shown, using estrogen receptor + I cells, expression 0 various lipoxygenases (LO) and cyclooxygenase mRNA espression. Furthermore, inhibition of the LO pathway induce apoptosis. We identified that blocking other lipid metabolism enzymes caused cells to accumulate in Go/G1 phase of the cell cycle. We synthesized new classes of bioactive lipid targeting inhibitors. These water soluble, stable drugs effectively blocked proliferation in breast cancer cultures yet showed little toxicity in bone marrow cultures. Mice were given regime for 3 - 10 weeks of the HPA-Na drug; necropsy revealed no toxicity other than hair lossat the site of drug administration. We have identified cross talk between MAP kinase pathway and arachidonic acid metabolismand have extensively characterized different fatty acid binding proteinsand find patterns unique to normal, localized or metastatic tumors. This finding potential for diagnosis of breast cancer. These important mechanistic studies open up new avenues for selection of possible drug treatments and regimens to combat breast cancer.