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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Ravacci, Graziela Rosa [1, 2] ; Brentani, Maria Mitzi [1] ; Tortelli, Jr., Tharcisio [1] ; Torrinhas, Raquel Suzana M. M. [2] ; Saldanha, Tatiana [3] ; Torres, Elizabeth Aparecida F. S. [4] ; Waitzberg, Dan Linetzky [2]
Total Authors: 7
[1] Univ Sao Paulo, Sch Med, Dept Oncol, BR-01245903 Sao Paulo - Brazil
[2] Univ Sao Paulo LIM 35, Sch Med, Dept Gastroenterol, BR-01246903 Sao Paulo - Brazil
[3] Univ Fed Rural Rio de Janeiro, Dept Food Technol, BR-23890000 Rio De Janeiro - Brazil
[4] Univ Sao Paulo LIM 35, Publ Hlth Fac, BR-01246903 Sao Paulo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: JOURNAL OF NUTRITIONAL BIOCHEMISTRY; v. 24, n. 3, p. 505-515, MAR 2013.
Web of Science Citations: 24

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. (C) 2013 Elsevier Inc. All rights reserved. (AU)