PREVENTION OF HER2+ breast cancer may lie in n-3 Polyunsaturated fatty acids

[Lani]

J Lipid Res. 2013 Sep 19. [Epub ahead of print]
Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice.
Zou Z, Bellenger S, Massey KA, Nicolaou A, Geissler A, Bidu C, Bonnotte B, Pierre AS, Minville-Walz M, Rialland M, Seubert J, Kang JX, Lagrost L, Narce M, Bellenger J.
Source
Universite de Bourgogne, France;
Abstract
Overexpression of the tyrosine kinase receptor ErbB2/HER2/Neu, occurs in 25% to 30% of invasive breast cancer (BC) with poor patient prognosis. Due to confounding factors, inconsistencies still remain regarding protective effects of n-3 polyunsaturated fatty acids (PUFA) on BC. We therefore evaluated whether fat-1 transgenic mice, endogenously synthesizing n-3 PUFA from n-6 PUFA, 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 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 when they continued to grow up in the WT. This prevention can be related in part to significant repression of the HER2/beta-catenin signaling pathway and formation of significant levels of n-3 PUFAs derived bioactive mediators (particularly 15-HEPE, 17-HDHA and PGE3) in the tumor of fat-1 mice compared to WT. 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.
KEYWORDS:
Breast cancer, Cancer, Eicosanoids, HER2 signaling pathway, Mammary gland, Omega-3 fatty acids, PUFA-derived mediators, Prostaglandins, fat-1 mice, n-3 PUFA

PMID: 24052576

[sarah]

Hello,
what does this mean?
thanks
sarah

[Lani]

In a very artificial construct, implanting tumor cells into mice specially bred to transform the n6 fatty acids they were consuming in their diets into n3 fatty acids, the tumors they were able to grow prior to starting that diet totally disappeared.

When looking for what was responsible for the phenomenon they not only implicated the down regulation of her2 signalling by n3 fatty acids, but, confusingly to me, among other things, the upregulation of PGE3, a prostaglandin. As prostaglandins usually have the opposite effect, I will need to get the original article and read it piecemeal in order to understand this more fully.

Hope this helps!

PS humans cannot perform the same trick as these genetically altered mice, ie transforming the "bad"pufas to "good" pufas, as I understand it

[Lani]

from the article:
These mice carry the fat-1 gene from the roundworm Caenorhabditis elegans, encoding a n-3 PUFA desaturase, absent in mammals, that catalyzes conversion of n-6 into n-3 PUFA (22). Therefore, these mice have endogenously elevated n-3 PUFA tissue content and exhibit lower n-6/n-3 PUFA ratio compared to their wild-type (WT) littermates when maintained on a high n-6 PUFA diet. This contrasts feeding procedures using fish oil supplementation, which may bring confounding factors attributed in differences in the dietary composition. Hence, the fat-1 transgenic mouse model is a useful in vivo system for giving new insights of the role of n-6/n-3 fatty acid ratio in BC tumorigenesis.
...
When PGE2 has been shown to promote cancer development (51, 52) PGE3 has been found to have anticancer effects (53). Our results suggest that PGE3 and 17-HDHA might be anticancer metabolites, and these generated metabolites from EPA and DHA respectively may underlie the antitumor effect observed in the fat-1 transgenic mice. However, the concentration of PGE3 in the tumors of the fat-1 animals did not reach that of PGE2 suggesting that there is a role for AA-derived lipid mediators that cannot be totally replaced by EPA-derived lipid metabolites, EPA competing with AA acid as substrate for metabolite production. Interestingly, our in vitro experiments showed that addition of
14
17-HDHA downregulated HER2 and HER3 protein expression. Moreover, c-Myc expression was dramatically decreased by PGE2, PGE3 and 17-HDHA exposure.
These results suggest that PGE3 and 17-HDHA are anticancer mediators, and generation of PGE3 and 17-HDHA from n-3 PUFA may underlie the antitumor effect observed in fat-1 transgenic mice.

[Becky]

Its RB and Omega 3/fish oil! Thanks Lani

[Ellie F]

Thanks folk for the explanation. I read it several times and thought it was about the protective factors of omega 3. Not sure if it directly correlates to humans.
Ellie

[StephN]

Lani -
Thank you for the summaries.
I am trying to see the use of this knowledge in either staving off the onset of HER2 BC where there is a known risk, as well as aiding those who have progression of the disease knock it back.

Maybe that is too big a 'bite" at this point and I am getting ahead of things. But, I DID make changes in the ratios of my Omegas. Had never taken anything like fish oil till after stage IV although I did eat a good amount of wild caught. Also exchanged the vegetable oils for VERY high quality olive oil for the most part.

We now know that a person can lack some important element in processing many kinds of foods. Actually a lot is known about the breaking down and use by our bodies of vitamins and various supplements.

Wonderful to see how many directions are showing at least a glimmer of promise in understanding further our disease.

[europa]

Becky...what's RB?

[Becky]

RB is a member here who is an Omega 3 and Vitamin D expert who posts these findings alot. If you search his posts, you will learn alot

[R.B.]

^ Thanks Becky - nerd may be a better description than expert (-: - I am not even sure what an expert is - the more I read the more I realise how complex the body is - several lifetimes and several networked brains :) would not be enough :( - and arguably many 'experts' for a host of often 'good' reasons are not as widely read as they might be, and there is a tendency for a host of reasons for people to want to be seen to support the status quo even if in their personal space they question the wisdom of it - historical science provides lots of examples - but happily things do change slowly - Do many now believe the sun whizzes round the earth !

And yes you got succinctly to the point of this trial - simplistically these mice make their own fish / krill oil. :) - and they did not have much Omega 6 in their diet, part of which they turned into Omega 3s

For a bit more detail please see the Greek Diet Omega 3 and 6 thread

http://her2support.org/vbulletin/showthread.php?t=24410&page=21 26th September