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.

Lipidomic study of cell lines reveals differences between breast cancer subtypes

“…The cell line that was most dissimilar from the other cell lines based on both PCA and dendrogram was SK-BR-3 cell line. SK-BR-3 is a representative of HER2 overexpressing tumor subtype that is known to have increased FASN activity resulting in increased lipid synthesis and changes in the lipidome [43,44]. The clustering verified that BC subtypes could be distinguished based on the lipidome and suggests that there is within-subclass variation in the lipidome.…”

Adipose-Derived Fatty Acid-Binding Proteins Plasma Concentrations Are Increased in Breast Cancer Patients

“…Despite these data, there are no other reports describing the association of circulating FABP4 and breast cancer or even other cancer types. Furthermore, some recent publications have addressed the possible function of FABP4 in breast cancer , suggesting a putative role for this molecule in this pathology. These results are emerging with an exciting role for circulating FABP4 in breast cancer progression because circulating FABP4 would play a role in either fatty acid transport or activating key survival and proliferation pathways.…”

“…Exogenous FABP4 activates the cell proliferation of breast cancer cells and induces FABP5 and cluster of differentiation 36 (CD36) expression in MCF7 cells . Moreover, the overexpression of human epidermal growth factor receptor 2 (HER2) increases FABP4 levels , and FABP4 expression is high in HER2‐positive breast tumors . These results suggest a role for circulating FABP4 in breast cancer.…”

The Pharmacological Effect of Omega-3 Fatty Acids Prevent Cancer Progression in Colon and Breast Cancer

“…HER2 over expression leads to up regulation of Bcl-2, Bcl-xL, Mcl-1, and suppresses p53-mediated apoptosis by up regulation of MDM2 and activation of AKT [35]. An in vitro study has indicated DHA inhibits HER2 activity and Akt signaling molecules leading to cell death [36].…”