Efforts to exploit the dependence of tumors of fatty acids (FA) have thus far focused only on inhibiting FA synthesis. We have demonstrated that, in addition to the "lipogenic" apparatus, tumors are equipped to acquire circulating, diet-derived FAs using a "lipolytic" pathway. This employs the secreted enzyme lipoprotein lipase (LPL), which releases FAs from lipoproteins, and CD36, the channel for FA uptake. Alternatively, LPL may act as a nonenzymatic linker to facilitate lipoprotein endocytosis by binding to a cell surface heparin sulfate proteoglycan. We have demonstrated brisk LPL expression in all tumors examined to date (n=181). Our overarching hypothesis is that LPL-mediated FA uptake provides alternative mechanisms for FA acquisition by tumors that fuel growth and metastasis. We propose four Aims to test this idea in vivo. First we will define the role of LPL in the PyMT mouse breast cancer model combined with LPL-KO. PyMT tumors express abundant LPL and metastasize to lung, a tissue rich in LPL. Mice on low- or high-fat diets will be assessed for tumor growth and metastasis, and the phospholipid composition of tumor plasma membranes will be comprehensively analyzed. The diets will test the idea that LPL is a key determinant of the tumor-promoting effect of dietary fat. Second, we will use xenografts of tumor cells with low and high LPL expression to examine the relevance of tumor-associated LPL, in the absence of genotype-related differences in the tumor host. The cells will also be used to determine the relative contributions of lipid synthesis vs. uptake to tumor cell anabolism using 13C-labeled substrates. Third, we will use PyMT x CD36-KO mice to examine the impact of CD36 on tumor growth and metastasis in the context of the diets. Fourth, we will determine whether the lipolytic pathway can subvert the anti-cancer effects of FA synthesis inhibition. The existence of two pathways for lipid acquisition by tumors raises the concern that targeting either one alone will be ineffective. We will administer the FA synthesis inhibitor Triclosan to PyMT mice on low- or high-fat feeding to assess this. We will also assess the impact of simultaneously targeting FA production and uptake. These studies will provide mechanistic insights into the relative importance of lipid synthesis and uptake by tumors and the impact of dietary fat on tumor biology. Overall, this work will address major questions posed by our recent discovery of a "lipolytic" tumor phenotype, and will provide guidance for drug development efforts aimed at clinical exploitation of the dependence of tumors on FA.

Public Health Relevance

It is well established that most tumors, including breast cancer, require a supply of fatty acids for growth and survival. Thus far, investigative attention has focused solely on targeting de novo fatty acid synthesis, but we have now demonstrated that tumors are also universally equipped to obtain exogenous, diet-derived fatty acids from the blood stream, by expressing the enzyme lipoprotein lipase (LPL) and the fatty acid uptake channel CD36. This project will define the functional significance of the LPL/CD36 mechanism in mouse models of breast cancer, and its interaction with dietary fat and pharmacological fatty acid synthesis inhibition. The information will provide not only mechanistic insights, but will guide the development of drugs designed to target the requirement for fatty acids.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
McGowan, Margit M; Eisenberg, Burton L; Lewis, Lionel D et al. (2013) A proof of principle clinical trial to determine whether conjugated linoleic acid modulates the lipogenic pathway in human breast cancer tissue. Breast Cancer Res Treat 138:175-83
Zaidi, Nousheen; Lupien, Leslie; Kuemmerle, Nancy B et al. (2013) Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog Lipid Res 52:585-9
Kuemmerle, Nancy B; Rysman, Evelien; Lombardo, Portia S et al. (2011) Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol Cancer Ther 10:427-36
Olsen, Arne M; Eisenberg, Burton L; Kuemmerle, Nancy B et al. (2010) Fatty acid synthesis is a therapeutic target in human liposarcoma. Int J Oncol 36:1309-14
Donnelly, Christina; Olsen, Arne M; Lewis, Lionel D et al. (2009) Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells. Nutr Cancer 61:114-22