The breast cancer microenvironment and lipoprotein lipase: Another negative notch for a beneficial enzyme?

Fig. 1. Lipogenesis and lipolysis pathways for fatty acid acquisition by tumor cells. The process of lipolysis involves the exogenous uptake of fatty acids facilitated by lipoprotein lipase (LPL) anchored to heparan sulfate proteoglycans (HSPG). LPL hydrolyzes fatty acids from triacylglycerol‐rich lipoproteins, such as very low‐density lipoproteins (VLDL), and the uptake of fatty acids by the cell is facilitated by the transmembrane protein transporter CD36. LPL also assists in receptor‐mediated endocytosis for intracellular hydrolysis lipids from lipoproteins to yield fatty acids. The process of lipogenesis involves the exogenous uptake of glucose, by glucose transporter 4 (GLUT4), for the de novo synthesis of fatty acids from glucose. FAS, fatty acid synthase; VLDLR, very low‐density lipoprotein receptor.

Fig. 2. Kaplan–Meier plot of the probability of survival over time for subjects with high or low expression of LPL mRNA within breast tumors assessed by RNAseq. RNAseq datasets for all types of breast cancer tumors primarily from The Cancer Genome Atlas database were examined for LPL mRNA expression, using kmplot online software (http://www.kmplot.com/) [13]. Subjects were defined as high expressors or low expressors of LPL mRNA based on the automatic calculation of the upper and lower quartiles of the arbitrary values of RNAseq data. Hazard ratios and statistical analyses were calculated with the online software, as previously described [13].

Fig. 3. Kaplan–Meier plots of the probability of survival over time for subjects with high or low expression of LPL mRNA within basal and luminal breast tumors assessed by RNAseq. RNAseq datasets from The Cancer Genome Atlas database for (A) basal‐type tumors, (B) luminal A‐type tumors, and (C) luminal B‐type tumors were examined for LPL mRNA expression, using kmplot online software (http://www.kmplot.com/) [13]. Subjects were defined as high expressors or low expressors of LPL mRNA based on the automatic calculation of the upper and lower quartiles of the arbitrary values of RNAseq data. Hazard ratios and statistical analyses were calculated with the online software, as previously described [13].

Fig. 4. LPL activity from the media of breast tumor cell lines in the absence or presence of heparin. Breast cancer cell lines were incubated for 30 min. in the absence or presence of heparin within serum‐free media. Heparinized media from HEK‐293T cells transiently transfected to express LPL were used as a positive control. Media were examined for LPL activity using a resorufin ester substrate. Data are presented as the mean of triplicate experiments ± standard deviation. *P < 0.05 using an unpaired t‐test. Experimental design and details are available within the Materials and methods.

Fig. 5. Analysis of LMF1 mRNA expression in breast cancer cell lines, primary breast tumor samples, and normal breast tissue. Gene expression data from 20 breast cancer cell lines, 31 breast cancer patient samples, and six normal breast tissue samples were obtained from the Gene Expression Omnibus database. LMF1 probe IDs were obtained and used to filter and average the gene expression data. Gene expression data were analyzed by complete linkage hierarchical clustering using genesis 1.8.1 [19]. Details of the analysis are available within the Materials and methods.

Fig. 6. Hypothesis for the role of LPL in the breast cancer microenvironment. Cell surface‐associated LPL, from either breast cancer cells or surrounding adipose tissue, will hydrolyze lipoprotein lipids to yield smaller lipoproteins and lipid hydrolysis products (including unesterified fatty acids, acylglycerides, and lysophospholipids). We hypothesize that these products will result in breast cancer cell proliferation and metastasis, leading to a reduced prognosis.