trans-10-cis-12-conjugated-linoleic-acid and Breast-Neoplasms

Conjugated linoleic acids (CLAs) are natural dairy food components that exhibit a unique body of potential health benefits in animals and man, including anti-cardiovascular disease and anti-cancer effects. Several studies have demonstrated that fatty acid synthase (FAS) levels (protein and mRNA) are over expressed in many carcinomas. Sterol regulatory element binding proteins (SREBPs) are transcription factors that regulate genes involved in lipid metabolism, including FAS.. Breast cancer cell lines, MCF-7 and MDA-MB-231 were treated with CLAs to investigate the regulation of SREBP-1c and FAS expression.. In MDA-MB-231 cells, SREBP-1c and FAS were co-ordinately decreased by treatment with 25 μM CLA 9-11 and 10-12. In MCF-7 cells, the decrease in SREBP-1c and FAS expression was dependant on the concentration of CLA used.. The data suggest a differential effect of CLAs on SREBP-1c and FAS in estrogen receptor-positive (MCF-7) compared to estrogen receptor-negative (MDA-MB-231) breast cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Fatty Acid Synthase, Type I; Female; Gene Expression Regulation, Neoplastic; Humans; Linoleic Acids, Conjugated; Neoplasm Proteins; Osmolar Concentration; Protein Isoforms; Receptors, Estrogen; RNA, Messenger; Sterol Regulatory Element Binding Proteins

HER2-targeted therapy with the monoclonal antibody trastuzumab (Herceptin) has improved disease-free survival for women diagnosed with HER2-positive breast cancers; however, treatment resistance and disease progression are not uncommon. Current data suggest that resistance to treatment in HER2 cancers may be a consequence of NF-kappaB overexpression and increased COX2-derived prostaglandin E2 (PGE(2)). Conjugated linoleic acid (CLA) has been shown to have anti-tumor properties and to inhibit NF-kappaB activity and COX2.. In this study, HER2-overexpressing SKBr3 breast cancer cells were treated with t10c12 CLA. Protein expression of the HER2 receptor, nuclear NF-kappaB p65, and total and phosphorylated IkappaB were examined by western blot and immunofluorescence. PGE(2) levels were determined by ELISA. Proliferation was measured by metabolism of 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), and apoptosis was measured by FITC-conjugated Annexin V staining and flow cytometry.. We observed a significant decrease in HER2 protein expression on western blot following treatment with 40 and 80 microM t10c12 CLA (p<0.01 and 0.001, respectively) and loss of HER2 protein in cells using immunoflourescence that was most pronounced at 80 microM. Protein levels of nuclear NF-kappaB p65 were also significantly reduced at the 80 microM dose. This was accompanied by a significant decrease in PGE(2) levels (p = 0.05). Pretreatment with t10c12 CLA significantly enhanced TNFalpha-induced apoptosis and the anti-proliferative action of trastuzumab (p = 0.05 and 0.001, respectively). These data add to previous reports of an anti-tumor effect of t10c12 CLA and suggest an effect on the HER2 oncogene that may be through CLA mediated downregulation of COX2-derived PGE(2).

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cyclooxygenase 2; Dinoprostone; Female; Gene Expression; Genes, erbB-2; Humans; Linoleic Acids, Conjugated; Models, Biological; Receptor, ErbB-2; Transcription Factor RelA; Trastuzumab; Tumor Necrosis Factor-alpha