Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice

Abstract

Breast cancer (BC) remains one of the most threatening mortality factors throughout the world despite significant advancements in early detection and therapy. With a current mortality rate of 40%, over one million women worldwide will fall victim to BC. Four closely related transmembrane tyrosine kinase receptors (HER1, -2, -3, and -4) have been implicated in the pathogenesis of cancer including BC. Binding of small peptide ligand molecules to HER receptors triggers homo-or heterodimerization and autophosphorylation, which results in enhanced cell proliferation, migration, and invasion ( 1, 2 ) via the PI3K / AKT/ ␤ -catenin downstream signaling pathway ( 3 ). The HER2/HER3 heterodimer is considered to be the Abstract 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 wildtype (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 signifi cant repression of the HER2/ ␤ -catenin signaling pathway and formation of signifi cant 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

Activation of PPARγ2 by PPARγ1 through a functional PPRE in transdifferentiation of myoblasts to adipocytes induced by EPA

“…3B), indicating that EPA inhibits Wnt/b-catenin signaling by inducing the proteasomal degradation of b-catenin. Similar results were observed in cancer cells treated with EPA and other n-3 PUFA, 22,30,31 suggesting that n-3 PUFAs have the general effect to inhibit Wnt/ b-catenin signaling in both normal and tumor cells.…”

Prostaglandin E3 metabolism and cancer

“…These results could contribute to the mechanisms of anticancer activities of n-3 fatty acids. Furthermore, two studies using mice carrying the Fat-1 transgene, which restores the synthesis of n-3 fatty acids (EPA and DHA), inoculated with either mouse melanoma B16 cells or mouse HER2 positive breast cancer E0771 cells, showed that the development of melanoma and HER2 positive mammary gland tumors were substantially reduced after 15 days of cell inoculation while the tumors in the Fat-1 wild type (WT) mice continued to grow [79,90]. Interestingly, Xia et al demonstrated that the reduction of PGE 2 was moderate in the stromal tissues and stronger in the tumors in the Fat-1 WT mice, while PGE 3 was markedly increased in both the stromal and the tumor tissues in the Fat-1 transgenic mice with melanoma [79].…”

“…Interestingly, Xia et al demonstrated that the reduction of PGE 2 was moderate in the stromal tissues and stronger in the tumors in the Fat-1 WT mice, while PGE 3 was markedly increased in both the stromal and the tumor tissues in the Fat-1 transgenic mice with melanoma [79]. Similarly, there was notably increase in PGE 3 production in the mammary tumors of the Fat-1 transgenic mice compared to that in the Fat-1 WT mice [90]. The significant contribution of COX-2 to the chemopreventive activity of fish oil is further strengthened by recent findings revealing that higher consumption of n-3 PUFA (EPA and DHA) lowered the risk of aggressive prostate cancer with this effect being more pronounced in men carrying a particular COX-2 variant [14].…”

Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Postmenopausal Women

“…Additional mechanisms include reduced adhesion molecule expression and motility and improved insulin sensitivity [20,21]. A sum result is likely reduction in proliferation, increased apoptosis, and reduced mammary carcinogenesis [18,19,22]. …”