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Epidemiological studies suggest that metabolic disorders such as obesity and diabetes increase the risk of some cancers. The mechanistic link between these diseases and cancer, however, is not understood. Fatty acids can be an important source of ATP, via oxidation in mitochondria. They can also be esterified into many complex lipids, such as components of cell membranes, triglycerides (TG) or signaling molecules (e.g. ceramide). Of potential importance, many cancers show aberrant lipid metabolism, e.g. overexpression of fatty acid synthase. The abnormal lipid metabolism in cancer cells therefore, combined with the elevated plasma lipids in metabolic conditions, may contribute to cancer progression. To learn more about metabolism of fatty acids in cancer cells and its relationship with cell growth and survival, we studied the effect of exogenous oleate, the most common plasma fatty acid, on transformed (MDA MB 231) and non-transformed (MCF10A) breast cells in culture. We found that oleate (100 μM, delivered in complex with BSA) protects MDA MB 231 breast cancer cells from apoptosis induced by serum withdrawal. Moreover, short-term (6-24 h) preincubation of these cells with oleate promotes growth factor independent survival for many days after removal of oleate from the culture medium. The effect is dose dependent since the period of survival is related to the concentration of oleate used (greater then 60% of cells still alive at day 2, 3, 5 and 9 following preincubation with oleate at 0, 33, 50, 100 μM, respectively). Interestingly, fatty acids metabolism is markedly different between the two cell lines. Oleate exposure leads to rapid accumulation of intracellular TG and formation of lipid droplets in MDA MB 231 cells only. TG accumulation reflects the oleate concentration used and correlates with the duration of serum-free cell survival. Oleate has no long-term effect on cell proliferation, so its effect appears to be anti-apoptotic. The non-transformed MCF10A cells, do not accumulate TG, most likely due to high rates of fat oxidation (10 times that observed in MDA MB 231 cells) and are not protected by oleate and die by apoptosis. The survival mechanism induced by oleate in MDA MB 231 cells in the absence of growth factors is under investigation. Oleate released from lipid droplets by lipolysis can perhaps be used as an alternative energy source. This is however unlikely in MDA MB 231 cells, as these cells poorly oxidize fatty acids and metabolize glucose at high rates irrespective of the presence of serum. Overall the results are consistent with a role for altered lipid metabolism in the long-term survival of some tumor cells. We are presently testing if the survival effect described here applies to other cancer cell lines. Increased knowledge of fatty acid metabolism in cancer cells may open new possibilities for cancer prevention, treatment and improvement in prognosis.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]