Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice.
Overexpression of the tyrosine kinase receptor, ErbB2/HER2/Neu, occurs in 25-30% of invasive breast cancer (BC) with poor patient prognosis. Due to confounding factors, inconsistencies still remain regarding the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on BC. We therefore evaluated whether fat-1 transgenic mice, endogenously synthesizing n-3 PUFAs from n-6 PUFAs, were protected against BC development, and we then aimed to study in vivo a mechanism potentially involved in such protection. E0771 BC cells were implanted into fat-1 and wild-type (WT) mice. After tumorigenesis examination, we analyzed the expression of proteins involved in the HER2 signaling pathway and lipidomic analyses were performed in tumor tissues and plasma. Our results showed that tumors totally disappeared by day 15 in fat-1 mice but continued to grow in WT mice. This prevention can be related in part to significant repression of the HER2/β-catenin signaling pathway and formation of significant levels of n-3 PUFA-derived bioactive mediators (particularly 15-hydroxyeicosapentaenoic acid, 17-hydroxydocosahexaenoic acid, and prostaglandin E3) in the tumors of fat-1 mice compared with WT mice. All together these data demonstrate an anti-BC effect of n-3 PUFAs through, at least in part, HER2 signaling pathway downregulation, and highlight the importance of gene-diet interactions in BC.
Université de Bourgogne, UFR Sciences de la Vie, de la Terre et de l'Environnement, Dijon, France.
Zuquan
Z
Zou
Sandrine
S
Bellenger
Karen A
KA
Massey
Anna
A
Nicolaou
Audrey
A
Geissler
Célia
C
Bidu
Bernard
B
Bonnotte
Anne-Sophie
AS
Pierre
Mélaine
M
Minville-Walz
Michaël
M
Rialland
John
J
Seubert
Jing X
JX
Kang
Laurent
L
Lagrost
Michel
M
Narce
Jérôme
J
Bellenger
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000235:genetics*; D015525:Fatty Acids, Omega-3 / Q000097:blood / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D029742:Caenorhabditis elegans Proteins; D004281:Docosahexaenoic Acids; D044943:Fatty Acid Desaturases; D015525:Fatty Acids, Omega-3; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C489427:MYC protein, human; C466741:fat-1 protein, C elegans; C581292:ERBB3 protein, human
n-3 tissue enrichment; polyunsaturated fatty acid-derived mediators; xenograft prevention