α-linolenic acid and docosahexaenoic acid, alone and combined with trastuzumab, reduce HER2-overexpressing breast cancer cell growth but differentially regulate HER2 signaling pathways.

Julie K Mason,Ashleigh K A Wiggins,Lilian U Thompson,Shikhil Kharotia,Sukhpreet Klaire

doi:10.1186/s12944-015-0090-6

Julie K Mason, Ashleigh K A Wiggins + Show 3 more

Open Access

https://doi.org/10.1186/s12944-015-0090-6

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Journal: Lipids in Health and Disease	Publication Date: Aug 18, 2015
Citations: 69	License type: cc-by

Affiliation: University of Toronto

Abstract

BackgroundDiets rich in the n-3 fatty acid alpha-linolenic acid (ALA) have been shown to reduce breast tumor growth, enhance the effectiveness of the HER2-targeted drug trastuzumab (TRAS) and reduce HER2 signaling in mouse models. It is unclear whether this is due to direct effects of ALA or due to its long-chain n-3 fatty acids metabolites including docosahexaenoic acid (DHA).MethodsThe ability of HER2-overexpressing BT-474 human breast cancer cells to convert ALA to long-chain n-3 fatty acids was determined by measurement of phospholipid fatty acids by gas chromatography following treatment with 100 μM ALA. The effects of 96 h treatment with ALA or DHA, at serum levels seen in mice (50–100 μM), alone and combined with TRAS (10 μg/ml), on BT-474 cell growth measured by trypan blue exclusion, apoptosis measured by flow cytometric analysis of Annexin-V/7-AAD stained cells (ALA and TRAS treatment only) and protein biomarkers HER2 signaling measured by western blot were determined.ResultsALA-treated BT-474 cells had higher phospholipid ALA but no increase in downstream n-3 metabolites including DHA. Both ALA and DHA reduced cell growth with and without TRAS. ALA had no effect on apoptosis. ALA and DHA showed opposite effects on Akt and MAPK phosphorylation; ALA increased and DHA decreased phosphorylation.ConclusionsTogether these data suggest that, while both ALA and its DHA metabolite can reduce HER2-overexpressing breast cancer growth with and without TRAS, they demonstrate for the first time that DHA is responsible for the effects of ALA-rich diets on HER2 signaling pathways.

Highlights

Diets rich in the n-3 fatty acid alpha-linolenic acid (ALA) have been shown to reduce breast tumor growth, enhance the effectiveness of the Human epidermal growth factor receptor 2 (HER2)-targeted drug trastuzumab (TRAS) and reduce HER2 signaling in mouse models
Together these data suggest that, while both ALA and its docosahexaenoic acid (DHA) metabolite can reduce HER2overexpressing breast cancer growth with and without TRAS, they demonstrate for the first time that DHA is responsible for the effects of ALA-rich diets on HER2 signaling pathways
Protein biomarkers of HER2 signaling pathways Figure 2 shows that pHER2/HER2 expression was not affected by ALA and TRAS alone and in combination at 48 and 96 h

Summary

Introduction

Diets rich in the n-3 fatty acid alpha-linolenic acid (ALA) have been shown to reduce breast tumor growth, enhance the effectiveness of the HER2-targeted drug trastuzumab (TRAS) and reduce HER2 signaling in mouse models. FSO diets at 4 % [11] and 8 % [13] levels enhance the effectiveness of the HER2targeted drug trastuzumab (TRAS) in reducing tumor growth and cell proliferation and increasing apoptosis of BT-474 tumors This beneficial interaction is at least partially due to reduced signaling through HER2 as indicated by reduced activation of HER2, Akt and MAPK [11]. FSO has been shown to reduce MAPK and Akt signaling in MCF-7 xenografts [7, 9] Together, this suggests that ALA-rich FSO may be a beneficial complementary treatment approach in breast cancer

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