Distinct pattern of one-carbon metabolism, a nutrient-sensitive pathway, in invasive breast cancer: A metabolomic study.

Altered cell metabolism is a hallmark of cancer and critical for its development. Particularly, activation of one-carbon metabolism in tumor cells can sustain oncogenesis while contributing to epigenetic changes and metabolic adaptation during tumor progression. We assessed whether increased one-carbon metabolism activity is a metabolic feature of invasive ductal carcinoma (IDC). Differences in the metabolic profile between biopsies from IDC (n = 47) and its adjacent tissue (n = 43) and between biopsies from different breast cancer subtypes were assessed by gas spectrometry in targeted (Biocrates Life Science ® ) and untargeted approaches, respectively. The metabolomics data were statistically treated using MetaboAnalyst 4.0, SIMCA P+ (version 12.01), Statistica 10 software and t test with p < 0.05. The Cancer Genome Atlas breast cancer dataset was also assessed to validate the metabolomic profile of IDC. Our targeted metabolomics analysis showed distinct metabolomics profiles between IDC and adjacent tissue, where IDC displayed a comparative enrichment of metabolites involved in one-carbon metabolism (serine, glycine, threonine, and methionine) and a predicted increase in the activity of pathways that receive and donate carbon units (i.e., folate, methionine, and homocysteine). In addition, the targeted and untargeted metabolomics analyses showed similar metabolomics profiles between breast cancer subtypes. The gene set enrichment analysis identified different transcription-related functions between IDC and non-tumor tissues that involved one-carbon metabolism. Our data suggest that one-carbon metabolism may be a central pathway in IDC and even in general breast tumors, representing a potential target for its treatment and prevention.

Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells.

In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of "de novo" FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.

Lipid raft disruption by docosahexaenoic acid induces apoptosis in transformed human mammary luminal epithelial cells harboring HER-2 overexpression.

In HER-2-overexpressing breast cells, HER-2 receptors exist on the cell surface as monomers, homodimers and heterodimers. For signal activation and transduction to occur, HER-2 must be localized to lipid rafts. Therefore, we hypothesized that the amount of lipid rafts on the cell membrane would be a factor in HER-2 signaling. To test this, we used HB4a (an untransformed human mammary epithelial cell line) and HB4aC5.2 cells. HB4aC5.2 cells are HB4a derivatives that have been transfected with five copies of pJ5E.c-ErbB-2 and express approximately 900 times more HER-2 than HB4a cells. In these cells, HER-2 overexpression was accompanied by increased lipid rafts in cell membranes, a hyperactivation of downstream Akt and ERK1/2 proteins, and an increased rate of cell growth compared to HB4a. In addition, HER-2 overexpression was associated with an increased activation of FASN, a key enzyme involved in cellular lipogenesis. Its final product, palmitate, is frequently used to synthesize lipid rafts. We further hypothesized that treatment with docosahexaenoic acid (DHA), an omega-3 fatty acid, would disrupt the lipid rafts and lead to a growth arrest. In HB4aC5.2 cells, but not HB4a cells, we found that DHA treatment disrupted lipid raft; inhibited HER-2 signaling by decreasing activation of Akt, ERK1/2 and FASN proteins; and induced apoptosis. Although little is known about lipid rafts, our data support the idea that disturbances in these microdomains induced by DHA may represent a useful tool for controlling the signaling initiated by HER-2 receptors and its therapeutic potential in the treatment of HER-2 positive breast cancer.

Complementarity of Subjective Global Assessment (SGA) and Nutritional Risk Screening 2002 (NRS 2002) for predicting poor clinical outcomes in hospitalized patients.

BACKGROUND & AIMS: We evaluated the ability of Nutritional Risk Screening 2002 (NRS 2002) and Subjective Global Assessment (SGA) to predict malnutrition related to poor clinical outcomes. METHODS: We assessed 705 patients at a public university hospital within 48 h of admission. Logistic regression and number needed to screen (NNS) were calculated to test the complementarity between the tools and their ability to predict very long length of hospital stay (VLLOS), complications, and death. RESULTS: Of the patients screened, 27.9% were at nutritional risk (NRS+) and 38.9% were malnourished (SGA B or C). Compared to those patients not at nutritional risk, NRS+, SGA B or C patients were at increased risk for complications (p=0.03, 0.02, and 0.003, respectively). NRS+ patients had an increased risk of death (p=0.03), and SGA B and C patients had an increased likelihood of VLLOS (p=0.008 and p<0.0001, respectively). Patients who were both NRS+ and SGA C had lower estimates of NNS than patients who were NRS+ or SGA C only, though their confidence intervals did overlap. CONCLUSIONS: The concurrent application of SGA in NRS+ patients might enhance the ability to predict poor clinical outcomes in hospitalized patients in Brazil.

Efeitos de diferentes emulsões lipídicas sobre a expressão de moléculas de superfície envolvidas no processo de apresentação de antígenos em células mononucleares humanas in vitro / Effects of different lipid emulsions over the expression of surface molecules involved in the antigen presenting process of in vitro human mononuclear cells

Emulsões lipídicas parenterais (EL) podem modular funções leucocitárias, influenciando a resposta imune. O processo de apresentação de antígenos por leucócitos ocorre pela expressão de moléculas de superfície específicas e constitui o ponto-chave para o desencadeamento de resposta imune eficiente / Parenteral lipid emulsion (LE) can modulate leukocytes function and modify immune response. The antigen presenting process by leucocytes occurs through the expression of specific surface molecules and constitutes the key point for the start of an efficient immune response...