title: Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells.
abstract: 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.
authors.affiliation: Department of Gastroenterology, School of Medicine, University of São Paulo, LIM 35, Avenida Doutor Arnaldo 455, Cerqueira Cesar, 01246-903 São Paulo, SP, Brazil ; Department of Radiology and Oncology, School of Medicine, University of São Paulo, São Paulo, SP, Brazil ; Support Group for Research on Food and Nutrition (NAPAN), University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Graziela Rosa
authors.initials: GR
authors.lastname: Ravacci
authors.affiliation: Department of Radiology and Oncology, School of Medicine, University of São Paulo, São Paulo, SP, Brazil ; Support Group for Research on Food and Nutrition (NAPAN), University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Maria Mitzi
authors.initials: MM
authors.lastname: Brentani
authors.affiliation: Cancer Institute of State of São Paulo (ICESP), São Paulo, SP, Brazil.
authors.forename: Tharcisio Citrângulo
authors.initials: TC
authors.lastname: Tortelli
authors.affiliation: Department of Gastroenterology, School of Medicine, University of São Paulo, LIM 35, Avenida Doutor Arnaldo 455, Cerqueira Cesar, 01246-903 São Paulo, SP, Brazil.
authors.forename: Raquel Suzana M M
authors.initials: RS
authors.lastname: Torrinhas
authors.affiliation: Department of Gastroenterology, School of Medicine, University of São Paulo, LIM 35, Avenida Doutor Arnaldo 455, Cerqueira Cesar, 01246-903 São Paulo, SP, Brazil.
authors.forename: Jéssica Reis
authors.initials: JR
authors.lastname: Santos
authors.affiliation: Pathology Department, São Paulo Federal University (UNIFESP-EPM), São Paulo, SP, Brazil.
authors.forename: Angela Flávia
authors.initials: AF
authors.lastname: Logullo
authors.affiliation: Department of Gastroenterology, School of Medicine, University of São Paulo, LIM 35, Avenida Doutor Arnaldo 455, Cerqueira Cesar, 01246-903 São Paulo, SP, Brazil.
authors.forename: Dan Linetzky
authors.initials: DL
authors.lastname: Waitzberg
mesh_terms: D000813:Anilides; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D004281:Docosahexaenoic Acids; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C457499:2-chloro-5-nitrobenzanilide