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

• Published in: BioMed research international 2015-01, Vol.2015 (2015), p.1-13
• Main Authors: Waitzberg, Dan Linetzky, Santos, Jéssica Reis, Torrinhas, Raquel Suzana M. M., Tortelli, Tharcisio Citrângulo, Brentani, Maria Mitzi, Ravacci, Graziela Rosa, Logullo, Angela Flávia
• Format: Article
• Language: English
• Subjects: Anilides; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biosynthesis; Breast cancer; Breast Neoplasms - metabolism; Cancer cells; Cell Line, Tumor; Colleges & universities; Docosahexaenoic Acids - pharmacology; Fatty acids; Female; Gene expression; Genetic aspects; Genotype & phenotype; Health aspects; Humans; Lipids; Medical prognosis; Metabolism; Observations; Phenotype; Receptor, ErbB-2 - metabolism; Trastuzumab - pharmacology; Triglycerides; Tumorigenesis; Unsaturated fatty acids
• ISSN: 2314-6133; 2314-6141
• DOI: 10.1155/2015/838652

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.