Breast cancer cells require fat for its survival and proliferation

It has long been known that obesity can increase the risk and worsen the outcome for breast cancer but it was not known exactly how this occurred. Fat provides cancer cells with the nutrients they need to fuel their growth, and by inhibiting the enzyme responsible for synthesizing fat, proliferation of cancer cells can be reduced (but not stopped!). To find out how to further slow (or stop) cancer growth, there needs to be and understanding of the underlying molecular mechanisms regarding fat uptake. Investigators from Dartmouth College and the Dartmouth-Hitchcock Norris Cotton Cancer Center have set out to understand exactly that for breast cancer. They have recently published their findings in the Journal of Lipid Research through an article titled “Endocytosis of very low-density lipoproteins: an unexpected mechanism for lipid acquisition by breast cancer cells”.

The researchers found that that breast cancer cells take up large quantities of fat that circulate in the blood stream, via lipoprotein lipase (LPL), an enzyme that breaks down triglycerides into fatty acids and oils. LDL equips breast cancer cells to take up fat, specifically very low density lipoproteins (VDLP).

When LPL were rendered inactive, the cancer cells take up significantly less VDLP, and their genetic signatures show a shift towards fatty acid synthesis and compensatory upregulation of other genes in the lipid uptake program. This finding explains that cancer cells have other means of getting their supply of fat. First, they are able to synthesize their own fat. Second, they have other channels of fat uptake.

The mechanism in which the cancer cell can manufacture their own reserve of fat is of utmost importance. Many academic- and pharma-based efforts are underway to use this finding as a therapeutic target.

The research team concluded that “this metabolic plasticity has important implications for the development of therapies aimed at the lipid dependence of many types of cancer, in that inhibition of fatty acid synthesis, may elicit compensatory upregulation of lipid uptake. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.

Lupien L, Bloch K, Kinlaw Wb et al., Endocytosis of very low-density lipoproteins: an unexpected mechanism for lipid acquisition by breast cancer cells. J. Lipid Res, 2019 doi: 10.1194/jlr.RA119000327