Increased lipogenesis is critical for self-renewal and growth of breast cancer stem cells: Impact of omega-3 fatty acids

Aberrant lipid metabolism has recently been recognized as a new hallmark of malignancy, but the characteristics of fatty acid metabolism in breast cancer stem cells (BCSC) and potential interventions targeting this pathway remain to be addressed. Here, by using the in vitro BCSC models, mammosphere-derived MCF-7 cells and HMLE-Twist-ER cells, we found that the cells with stem cell-like properties exhibited a very distinct profile of fatty acid metabolism compared with that of their parental cancer cells, characterized by increased lipogenesis, especially the activity of stearoyl-CoA desaturase 1 (SCD1) responsible for the production of monounsaturated fatty acids, and augmented synthesis and utilization of the omega-6 arachidonic acid (AA). Suppression of SCD1 activity by either enzyme inhibitors or small interfering RNA (siRNA) knockdown strikingly limited self-renewal and growth of the BCSC, suggesting a key role for SCD1 in BCSC proliferation. Furthermore, elevated levels of SCD1 and other lipogenic enzymes were observed in human breast cancer tissues relative to the noncancer tissues from the same patients and correlated with the pathological grades. Interestingly, treatment of BCSC with omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, effectively downregulated the expression of the lipogenic enzymes and markedly suppressed BCSC self-renewal and growth. Dietary supplementation of nude mice bearing BCSC-derived tumors with omega-3 fatty acids also significantly reduced their tumor load. These findings have demonstrated that increased lipogenesis is critical for self-renewal and growth of BCSC, and that omega-3 fatty acids are effective in targeting this pathway to exert their anticancer effect.