Cox2 and her-2

[fullofbeans]

I recently learned that Her2 & COX2 are intimately linked. I use to think, like many I beleive, that taking natural COX2 inhibitor (such as tumeric) was mostly related to reduce inflamation..but in fact it looks that it is mostly useful for HER2 people..more info on this aspect very welcome..


The inducible prostaglandin synthase isoform cyclooxygenase-2 (COX-2) is overexpressed in http://cancerpreventionresearch.aacrjournals.org/math/sim.gif40% of human breast carcinomas and in precancerous breast lesions, particularly in association with overexpression of human epidermal growth factor receptor 2 (HER2/neu). Experimental breast cancer can be suppressed by pharmacologic inhibition or genetic ablation of Cox-2, suggesting potential clinical utility of COX-2 inhibitors with respect to breast cancer. Importantly, several clinical trials have found reduced colorectal adenoma formation in individuals administered selective COX-2 inhibitors. However, such trials also identified increased cardiovascular risk associated with COX-2 inhibitor use. The goal of this research was to test whether improved chemopreventive efficacy could be achieved by combining submaximal doses of a selective COX-2 inhibitor and a retinoid X receptor–selective retinoid (rexinoid). The rate of HER2/neu-induced mammary tumor formation was substantially delayed by coadministration of the COX-2 inhibitor celecoxib (500 ppm in diet) and the rexinoid LGD1069 (10 mg/kg body weight; oral gavage) to MMTV/neu mice. Median time to tumor formation was increased from 304 to >600 days (P < 0.0001). The combination was substantially more effective than either drug individually. Similarly, potent suppression of aromatase activity was observed in mammary tissues from the combination cohort (44% of control; P < 0.001). Regulation of aromatase expression and activity by COX-derived prostaglandins is well established. Interestingly however, single agent LGD1069 significantly reduced mammary aromatase activity (71% of control; P < 0.001) without modulating eicosanoid levels. Our data show that simultaneous blockade of COX/prostaglandin signaling and retinoid X receptor–dependent transcription confers potent anticancer efficacy, suggesting a novel avenue for clinical evaluation

http://cancerpreventionresearch.aacrjournals.org/cgi/content/abstract/1/3/208

[R.B.]

Cox2 is one of the downstream enzymes that converts the long chain 20 carbon Omega 6 Arachidonic Acid to the inflammatory products.

It is also involved in hormone control as downstream products of Omega 6 ultimately regulate sex hormone production (with lots of other factors playing a part).

All of which is part of why excess Omega 6 and lack of Omega 3 arguably play a significant part in cancers.

If you search Cox2 in search above there have been over time quite a few links on the subject.

Cox blockers are being tested as adjunctive treatment in a number of cancers.

A problem is that once you have eaten Omega 6 it has to go somewhere
- Store it in fat
- Burn it
- Turn it into chemicals

Cox blockers are probably at best a diversion. Getting the raw material back within natures parameters is arguably a better starting point.

Thanks for the post Fullofbeans.


http://her2support.org/vbulletin/showthread.php?t=30984&highlight=cox2

[fullofbeans]

If I understand you well R.B one would not need Cox2 inhibitor if they did not eat much omega6 since Cox2 is only activated in the presence of omega6 needed to be converted. Is that really the main activator of Cox2?

You seem to link the final outcome to the production of aromatase, however the BC that are the most statistically affected by healthy life style (junk food full of omega 6) are the BC that are Er-... that said I am sure that there is other pathway as indeed inflamatory response is never good for anyone. (only playing the devil's fat advocate ;-))

Also I want to add to what I posted: maybe tumeric is actually more in use as an anti-angiogenic component in fact as oppose to an Cox2 inhibitor but perhaps performs both function I use to know but forgot..not important just eat the stuff!

[R.B.]

Hi Full of Beans,

Omega six is the raw material.

COX 2 is an enzyme that is part of the conversion process to prostaglandins. COX 2 products are made on demand as a result of requests received as chemical messengers triggered by a perceived need for inflammatory chemicals - things to mend immune threat etc.

Prostaglandins have a role in controlling aromatase and other enzymes involved in making sex hormones.

So no raw material, and COX 2 has nothing to help convert. Less Omega 6 must in the long term subject to body fat stores mean less downstream Omega 6 based inflammatory products.

Omega 3 also uses COX2 to make its own products. So more Omega 3 and some of the COX2 available production capacity will be diverted to Omega 3 products.

DHA also block the COX2 Omega 6 production line.

Drugs do the same thing by blocking COX2 from working. Clearly drugs can provide immediate relief but cannot remove excess omega six from the diet. Arguably the starting point of a long term strategy has to be sorting out the Omega 3 6 balance, and trials show doing that helps relieve inflammation and may reduce or for some even maybe eliminate the need for related drugs.

Is aromatase the only factor. Clearly no. In the greek diet thread there are a number of pathways connected to BC that respond to the Omega 3:6 balance. http://her2support.org/vbulletin/showthread.php?t=24410&highlight=greek+diet

The body is enormously complex so there are another factors too but excess Omega 6 and lack of 3 are a risk factor people can do something about and the risk reduction figures are suggest to be anything from 70% down depending on what trial you look at..

Clearly we are all different so please discuss dietary change with your Doctor and more so if on medication so you can properly assess plan and monitor.

[fullofbeans]

Hi R.B. thanks for your answer but..

1)
"COX 2 products are made on demand as a result of requests received as chemical messengers triggered by a perceived need for inflammatory chemicals "

Do yo know if the demand you refer to above are made ONLY by omega 6 and omega 3 oils ? i.e anything else triggers Cox2 production (chemical messager is the rather vague since all functions in our body are in effect triggered by chemical messages)

2)
"Omega 3 also uses COX2 to make its own products [..]
DHA also block the COX2 Omega 6 production line."

Would it be that omega 3 simply 'goes first' and Cox2 activity for omega6 will resume once the omega3 has been transformed. In which case taking more omega3 is not the answer (for downregulation of Co2x) but in fact limiting omega6 is.

3)
What is the omega3 product transformed into using Cox2? something not inflamatory unlike the omega6?

Many thanks R.B.

[R.B.]

Hi R.B. thanks for your answer but..

1)
"COX 2 products are made on demand as a result of requests received as chemical messengers triggered by a perceived need for inflammatory chemicals "

Do yo know if the demand you refer to above are made ONLY by omega 6 and omega 3 oils ? i.e anything else triggers Cox2 production (chemical messager is the rather vague since all functions in our body are in effect triggered by chemical messages)

Agreed chemical messengers is vague, but if you start to search you will find lots of things trigger production or activation of COX 2. The cells make and activate COX2 in response to lots of things.

The raw Omega 3 and 6 materials are stored in the cell membranes. Cells release Omega 3 and 6 in the ratio they are present in the cells and COX2 gets to work - more 6 in the cell membranes and you are going to get more six products.

So the trigger is not Omega 3 and 6 although there is talk of self fuelling cascades where I guess the ratio of 3 and 6 would either inhibit or encourage a 6 self fuelling cascade - more omega six product triggers more messengers triggers more cox 2 triggers more omega six product.


2)
"Omega 3 also uses COX2 to make its own products [..]
DHA also block the COX2 Omega 6 production line."

Would it be that omega 3 simply 'goes first' and Cox2 activity for omega6 will resume once the omega3 has been transformed. In which case taking more omega3 is not the answer (for downregulation of Co2x) but in fact limiting omega6 is.

Current wisdom as I understand it is Omega 6 gets priority in the line for access to the available COX2 enzyme (although I have seen others suggest it is Omega 3). Omega 6 chemical cascades require less energy that Omega 3 cascades. The greater the 3:6 imbalance towards Omega 6 the greater the priority of Omega 6.

DHA blocks both COX2 production and COX2 activation.

It gets mightily complicated and I struggle but the answer seems to be to balance the Omega 3 and 6 mother fats - which in most western diets means seriously cutting back on omega 6 AND ensure an adequate supply of the long chain Omega 3s which includes DHA.

3)
What is the omega3 product transformed into using Cox2? something not inflamatory unlike the omega6?

Omega 3s are transformed into similar products to the Omega 6s but they have very different roles and are not generally associated with `bad` inflammation. I have not seen a diagram of the family tree and bits here and there suggests they are not much studied. I suggest that they may have a bigger part to play at night and in sleep time repair growth etc. Omega 6s are connected with reproduction which requires some pretty dynamic activity etc, where as the 3s seem to play a more background role.


This is all very complex once you start reading about it as the products of these "simple" fats likley extend into every aspect of body function, and I struggle with it all and just try to give a sketch of what is going on.