title: Lipid raft disruption by docosahexaenoic acid induces apoptosis in transformed human mammary luminal epithelial cells harboring HER-2 overexpression.
abstract: 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.
authors: Department of Oncology Medical School, University of São Paulo, 01246-903 São Paulo, Brazil. grazielametanutri@gmail.com
authors: Graziela Rosa
authors: GR
authors: Ravacci
authors: Maria Mitzi
authors: MM
authors: Brentani
authors: Tharcisio
authors: T
authors: Tortelli
authors: Raquel Suzana M M
authors: RS
authors: Torrinhas
authors: Tatiana
authors: T
authors: Saldanha
authors: Elizabeth Aparecida F S
authors: EA
authors: Torres
authors: Dan Linetzky
authors: DL
authors: Waitzberg
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D050155:Lipogenesis; D042361:Mammary Glands, Human / Q000166:cytology; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004281:Docosahexaenoic Acids; D048052:Mitogen-Activated Protein Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human