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. 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. 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 (1Sliwkowski M.X. Schaefer G. Akita R.W. Lofgren J.A. Fitzpatrick V.D. Nuijens A. Fendly B.M. Cerione R.A. Vandlen R.L. Carraway 3rd, K.L. 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HER2 overexpression occurs in 25–30% of invasive BCs and is associated with a more aggressive phenotype and a poor patient prognosis with intrinsic resistance to endocrine and conventional chemotherapy (7Yu D. Hung M.C. Role of erbB2 in breast cancer chemosensitivity.Bioessays. 2000; 22: 673-680Crossref PubMed Google Scholar, 8Sørlie T. Perou C.M. Tibshirani R. Aas T. Geisler S. Johnsen H. Hastie T. Eisen M.B. van de Rijn M. Jeffrey S.S. et al.Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.Proc. Natl. Acad. Sci. USA. 2001; 98: 10869-10874Crossref PubMed Scopus (8540) Google Scholar). HER3 is often expressed together with HER2 in this disease (9Travis A. Pinder S.E. Robertson J.F. Bell J.A. Wencyk P. Gullick W.J. Nicholson R.I. Poller D.N. Blamey R.W. Elston C.W. et al.C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators.Br. J. Cancer. 1996; 74: 229-233Crossref PubMed Scopus (108) Google Scholar). While both receptors are considered promising targets for therapy, the overemphasis on HER2 has shadowed the important role of HER3 in resistance to HER2-targeted therapies (10Gianni L. Pienkowski T. Im Y.H. Roman L. Tseng L.M. Liu M.C. Lluch A. Staroslawska E. de la Haba-Rodriguez J. Im S.A. et al.Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.Lancet Oncol. 2012; 13: 25-32Abstract Full Text Full Text PDF PubMed Scopus (1631) Google Scholar, 11Schoeberl B. Faber A.C. Li D. Liang M.C. Crosby K. Onsum M. Burenkova O. Pace E. Walton Z. Nie L. et al.An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.Cancer Res. 2010; 70: 2485-2494Crossref PubMed Scopus (232) Google Scholar). an of the role of HER3 has the of D. 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R. fatty acids the activation of in breast cancer Oncol. 2004; 15: Full Text Full Text PDF PubMed Scopus Google Scholar). HER3 expression is associated with the n-3 effect in BC remains that or fatty acids an important role in the of inconsistencies and A. of and fatty acids and the of cancers of the breast and and of a of the J. 2003; PubMed Scopus Google Scholar). et D.J. S.E. B. of of and fatty acids with of breast PubMed Scopus Google Scholar) an of BC associated with n-3 PUFAs in a study with results confounding in and but fatty and is in D. has been that promotes proliferation, and apoptosis of BC cells S. M. and promotes and apoptosis of breast cancer has Res. 2000; Google and et M. M. R. A. M. effect of and in the of in Biol. 2010; PubMed Scopus Google Scholar) in a that the of with as as the in tumor and is still to the of n-3 PUFAs on BC prevention regarding from the the we evaluated the role of high n-3 in the pathogenesis of BC by in the transgenic fat-1 mice the fat-1 from the an n-3 in that of n-6 PUFAs into n-3 PUFAs J. L. fat-1 mice n-6 to n-3 fatty 2004; PubMed Scopus Google Scholar). these mice have endogenously n-3 and a compared with wild-type (WT) on a high n-6 This which confounding factors to in the the fat-1 transgenic is a in vivo for insights of the role of the fatty in BC We the of enhanced n-3 the of BC and the of the signaling we implanted these cells in the fat-1 transgenic and WT mice in to Our data that of BC by n-3 PUFAs be in part HER2 signaling pathway and were from The against and were from from The were from from and 17-hydroxydocosahexaenoic were from fat-1 mice were as J. L. fat-1 mice n-6 to n-3 fatty 2004; PubMed Scopus Google Scholar) and a The of the fat-1 in both by and fatty and WT were on a and in in and with a We to fat-1 transgenic mice and for this The and is high in with n-3 fatty of the the the transgenic a one in in fat-1 mice in WT All were to for the and of and by the of the of E0771 breast adenocarcinoma cells were from at E0771 cells were from a cancer in mice. This BC E0771 cell line to the cell that can be to breast tumors in fat-1 transgenic mice. The human BC cell and were by E0771 cells were in with with 2 and and cells were in with 2 and All these cells were in a of at the were in containing E0771 cells were with with and in the in or the with cells in of The day of the of E0771 cells day with a 2 or and to the tumor The fatty in and by as J. S. L. S. C. M. polyunsaturated fatty by of expression in the of J. 2004; PubMed Scopus Google Scholar). mediators were analyzed to the by et M. A. of and by PubMed Scopus Google Scholar, M. A. lipidomic of of bioactive mediators and related acids by 22: PubMed Scopus Google Scholar). tumor in of and were to and the for at at The to and by phase to the of performed on a fatty acids were analyzed a The performed a to a The were and by the as are expressed as The of cells to were evaluated by the cell to the and E0771 cells were and in at a of in containing to and then with to in a at and or for in containing to and the at After and of to and the for 2 The at on a are as cell of with were in and containing and were by and to After with in in were at with against and at a of in and for at with for the with performed the enhanced to the the in PUFA-derived mediators and the of E0771 cells in the mice, we the effects of and on the expression of and in these cells in After E0771 cells with or as cells were and performed to and The of expression as the for were and in were levels and of tumors were at performed an with and of with were in in for then with an and for 15 were with for The were then and with to for After were in and in were with 2 for and were After the were by the This is of an a for the a a and the which the were were by by the were and of the were by the of in This by the of a were expressed as the and for in the tumor growth tumor and fatty and mediators in tumor WT and fat-1 transgenic mice a The study of the tumor performed the by the that a of fatty acids is to the of we implanted E0771 BC cells into the fat-1 and WT mice and the of tumor in a in the tumor fat-1 transgenic and WT mice an of mice a tumor by day the tumors in fat-1 mice more and tumors disappeared at day contrast, the tumors in WT mice continued to grow that expression of fat-1 the growth of BC cells in vivo and results in tumor to the of HER2 and HER3 expression by a in fatty acids in fat-1 mice, tumor tissues were analyzed for the expression of HER2 and HER3 by in demonstrate that HER2 and HER3 were in the tumor tissues of fat-1 mice cell in the fat-1 tumor tissues compared with the WT mice a crucial role in and human cancer as a in and signaling part in with the which is a in BC W.J. 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We a in the expression were for expression in the fat-1 tumor We the expression of the of in expression in tumors of fat-1 mice, that be involved in factor a and is to be involved in the and of BC in and breast Biol. 2003; PubMed Scopus Google Scholar). in fat-1 tumor tissues a of expression compared with the WT mice. in transgenic expression of but apoptosis by an expression of in fatty of tumor levels of and in fat-1 transgenic mice compared with WT by the in tumors from fat-1 mice compared with WT despite the the results expression of fat-1 the transgenic in n-3 PUFAs at the of n-6 PUFAs, a We then n-6 and n-3 PUFA-derived from tumors n-6 n-3 and by to whether in tumor growth WT and fat-1 mice were associated with these in the and and and were at active levels tumors from fat-1 mice. were in tumors from WT mice. to and significant of and were in tumors of fat-1 mice. no significant in the of the but the levels of and were in the fat-1 transgenic mice compared with WT mice and of from showed fat-1 and WT mice are levels of n-3 PUFAs and and a of n-6 PUFAs in the from fat-1 transgenic mice compared with WT the in the transgenic mice data that in n-3 PUFAs at the of n-6 PUFAs, a in both the significant growth of E0771 cells in fat-1 transgenic mice, we whether n-3 PUFAs can BC cell in E0771 cells and human BC and were for to in a of cell in BC cell at more growth in E0771 cells in and of mortality with of and over of E0771 cells with to the mechanism by which n-3 PUFAs growth of BC to in the signaling pathway in cells in in HER2 and HER3 levels in and cell this effect in a and and of in and cells for HER2 and but and by the in E0771 cells with for HER3 expression results that on HER2 and HER3 but on the formation of HER2/HER3 the role of signaling in the the effect of n-3 PUFAs on the signaling in with the in a and in is by a containing in which is and to of whether of be of the of and kinase and were We that and in this more in E0771 cells in and whether of will the expression of we the in cells with Our results that expression in BC cell with for We the effect of on expression in Our results regarding expression that is and cell are with for at least results for the mechanism of n-3 PUFAs the signaling pathway in BC to the the in PUFA-derived mediators and the of E0771 cells in the mice, we the effects of and on the expression of and in these cells in in HER2 expression by the HER3 by both mediators and the of E0771 cells to and for data are with in vivo results that the levels in (particularly and in fat-1 tumors at least in part, the effect in fat-1 transgenic mice. 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Our results that and be and these from and the effect in the fat-1 transgenic mice. the of in the tumors of the fat-1 that of that is a role for mediators that be totally by with as for in showed that of HER2 and HER3 expression by and results that and are and of and from n-3 PUFAs the effect in fat-1 transgenic mice. data demonstrate a tumorigenesis effect of n-3 fatty at least in part activation of signaling pathway by n-3 PUFA-derived results the that expression of the fat-1 to of n-3 PUFAs, tumor This prevention by the signaling pathway and of n-3 PUFA-derived mediators in the tumors of fat-1 mice WT mice. results and by which n-3 PUFAs the of BC with conventional the with n-3 PUFAs be a to cancer for BC in which is and or of study that an n-3 be a for are for cancer for in and in and and for in and for of the and of for breast cancer acid, factor prostaglandin wild-type

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