Comparison of serum metabolomics in women with breast Cancer Prior to Chemotherapy and at 1 year: cardiometabolic implications | BMC Women’s Health

To our knowledge, this is one of the first studies to examine serum metabolite changes in women with early-stage BC from pre-chemotherapy to one year into survivorship. Our findings are a first step to a broader understanding of the biological changes associated with breast cancer treatments and survivorship. The metabolic changes in women between prior to chemotherapy and in survivorship were associated with lysine degradation, branched-chain amino acid synthesis, linoleic acid metabolism, tyrosine metabolism and biosynthesis of unsaturated fatty acids as the top 5 metabolic pathways. The biosynthesis of unsaturated fatty acids and linoleic acid were downregulated at T4 while branched-chain amino acid synthesis and lysine degradation were upregulated and tyrosine metabolism was differentially regulated. Levels of linoleic acid (LA), an omega-6 fatty acid and one of the essential polyunsaturated fatty acids (PUFAs) that are needed for cellular growth, were downregulated at T4. A pooled analysis of 20 studies in 39,740 subjects from 10 countries showed that higher plasma levels of LA are associated with a 43% reduced risk of diabetes, confirming other observations indicating an inverse relationship between dietary LA and the risk for T2D, which is, on the opposite, positively correlated with dietary saturated fatty acid [13]. Linoleic acid is first converted to gamma linolenic acid before ultimate conversion to arachidonic acid (20:4 n-6). Our data showed a reduction in both linolenic acid and arachidonic acid as well as metabolites associated with the arachidonic acid cascade (13-HODE, 20-carboxy arachidonic acid, and 2-hydroxy-9Z,12Z,15Z-octadecatrienoic acid). In addition to lower linoleic acid metabolites, we also observed a decrease in docosahexaenoic acid (22:6 n-3) an omega-3 PUFA. Thus, in general we observed a downregulation in fatty acid metabolism in survivorship. Elevated/increased dietary intake or tissue levels of LA is associated with a reduced incidence of cardiovascular diseases (mainly coronary artery diseases) and of new onset metabolic syndrome or type 2 diabetes. In addition, increased levels of steroid hormone synthesis metabolite lysophosphatidic acid have been implicated in the activation of signaling pathways regulating inflammation, oxidative stress and cell proliferation [18].

Branched-chain amino acid (BCAA) synthesis was upregulated: increased BCAA concentrations are found in various insulin-deficient and -resistant states, especially diabetes and obesity. An analysis of 139 serum metabolites found higher branched-chain AAs (BCAAs) leucine, isoleucine and valine, aromatic AAs 140 (AAAs) phenylalanine and tyrosine, as well as alanine, methionine, glutamate, lysine and proline in 141 volunteers with type 2 diabetes mellitus relative to non-diabetic controls. A recent study testing supplementation of both omega-3 and omega-6 PUFAs in breast cancer survivors found that omega-6 supplementation significantly reduced cancer related fatigue (CRF) [14]. Both supplements resulted in a decrease in the majority of serum AAs, including BCAAs and AAAs indicating the modifiability with nutritional intake [15]. Greater 10-year increases of branched-chain amino acids (BCAAs), diglyceride-/triglyceride-fragments, phosphatidylethanolamines, some vitamins, and bile acids were associated with higher type 2 diabetes risk and BCAAs have been linked to type 2 diabetes [16]. In cancer, BCAAs are involved in stimulating protein growth in tumors through activation of mTORC1 [17]. Abnormal regulation of FAs has been linked with cardiovascular conditions such as myocardial infarction and hypertrophy [18]. In addition, we noted decreased arachidonic acid metabolism at the one-year mark. An alteration in arachidonic acid (AA) metabolism is seen in the form of increased formation of pro-inflammatory eicosanoids and decreased production of anti-inflammatory lipoxins, type 2 diabetes mellitus, hypertension and endothelial dysfunction that are common with increasing age and aging-associated conditions. In all these conditions, the elevated levels of BCAAs and arachidonic acid metabolism noted in this study in are in the direction of heightened inflammatory responses.

Lysine degradation was upregulated: lysine is inversely correlated with numerous markers of inflammation including endotoxin, TLR-4, and IL-6. Moreover, acetylation of lysine is seen in states of insulin resistance and is also thought to play a role in immunomodulation. This inverse correlation may indicate an attempt to blunt the inflammatory response, leading to a depletion in lysine. Lysine and 2-AAA have also been implicated in the development of other CVD risk factors, such as obesity and metabolic syndrome. Previous studies have shown that circulating 2-aminoadipic acid (2-AAA) levels were associated with obesity and metabolic syndrome and had the ability to predict the risk of future T2D [19]. Aminoadipate is generated by lysine degradation and may also serve as a substrate for enzymes downstream of tryptophan metabolism. The current and previous findings collectively suggest that the mechanism behind metabolic syndrome and insulin resistance involves alterations in these metabolic pathways, distinct from pathways of BCAAs [20]. Lysine degradation attributed to microbiome changes in liver metabolism or the microbiome. In an animal model, lysine supplementation was shown to increase the spread of ER + breast cancer cells. Pipecolic acid (a metabolite of lysine) has been implicated in other cancers such as prostate and renal cell carcinoma, but its connection to breast cancer survivorship is currently unknown [21, 22]. In addition to perturbations in lysine regulation, we noted downregulated biosynthesis of unsaturated fatty acids: One study in women undergoing treatment for breast cancer with serum samples collected prior to chemotherapy (baseline; n = 50), just after the fourth cycle of chemotherapy (chemo-4; n = 40), and 6 months after beginning chemotherapy (6 M; n = 34) suggested a dysregulation of PUFAs post-chemotherapy with higher serum PUFAs associated with lower inflammation before, during, and after chemotherapy [23] suggests that n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation during cancer chemotherapy may improve outcomes related to chemotherapy tolerability, [24].