Attempting to increase rate of Herceptin efficacy,decrease rate of Hercptn resistance

[Gina]

every one's cup of tea due to its somewhat technical nature..I just wanted to say..the high level of exchange of ideas of free flowing brain-storming was superb.

I would love to get together in person with all who contributed sometime just to brain storm about these and so many other her-2 related issues.

Robin, in the early days, as Herceptin was so new and "resistance" to more traditional chemos quite common..., I must confess, that one reason I hesitated to take more herceptin than absolutely necessary was just that...I was worried about potential "resistance" no matter how you define that. The other reason was in the early days, no one really KNEW for sure what all the possible side effects of taking herceptin would eventually turn out to be, and as most of us were figured to be dead in a month or two anyway..NO ONE EVEN TALKED about the long - term side effects.

Fortunately, as we all know, the science behind HERCEPTIN was very sound and actually, thankfully, I encounter very few folks who really have any major problems caused by the herceptin. However, even early on, besides heart issues, there was another concern about herceptin's possible negative effects on the reproductive tract as in pelvic mets and increased CA 125's which as you know are often indicative of ovarian cancer. I only learned this early on because one of the gals who was detailed to do my complicated blood draws had been working as a cancer tumor marker researcher in a major research hospital where herceptin was being tested in various ways and one of the "complications" that kept showing up was an increase in CA 125 for women taking herceptin over extended periods of time...although, interestingly, at least in the group being studied...this increase in CA 125 did not always progress to ovarian cancer...but was common enough as were "PELVIC METS" to be noted.

Over the years, especially when I would take some herceptin in a row, I would get from time to time "complex" cysts on my ovaries. This worried me to no end. So much so, I even agreed to exploratory surgery, knowing the risks of worsening mets that often accompany surgery. What they found and took plenty of color pictures of ... was a perfect internal reproductive anatomy...absolutely perfect...samples taken everywhere revealed INFLAMATION but no cancerous or even pre-cancerous cells..., but unfortunately, no "cause" of the inflamation and highly vacuolated cells could be determined via pathology.

The color shot of my liver, which of course, was metastatic at the time...revealed the unexpected white lace -like patterns of the nearly 2-D Her-2 lesions that were there at the time...resting gently on a bed of otherwise absolutely red and healthy liver. It was so healthy, the surgeon, knowing of my past history with 12 metastatic liver lesions, could not believe its fortunate condition.

As for worrying about my ER-PR- cancer turning hormonal positive...it is strange that from my her-2 mediated disease, I worry more about what will happen to me when I enter natural menopause, as in my case, my continuing to produce estrogen has been one of the number one KEY factors that help keep my brand/variety of her-2 in control...I tested this many times, by seeing my markers slightly rise as my estrogen levels would drop before my cycle...also, when I had my primory 5cm tumor...even though none of my doctors would listen to me...it got much worse and grew more the week BEFORE my period as the estrogen levels dropped...you see, I have a completely different theory of estrogen from most folks in the cancer world. I actually think it is a good thing with my type of her-2 as estrogen has an inverse relationship to her-2...at least in my body--but is documented also in the literature...when estrogen is at normal levels (not excessive as I have never had that problem), but when they are at normal levels..her-2 tends to stay in check...when they drop, that is when I have to work harder to keep the markers down...

I have said this before, but I do believe a good percentage of us on this site share a common ancestor that goes WAY back to the early pre-out-of Africa settlements in eastern europe...we can trace our lineage back to a time when there were no grandmothers --to a time of perhaps something like a self-destruct gene..a time when "hominids" resembled their cousins much more closely, meaning that once the time of reproduction had past, so had bio-chemical usefulness and thus, early death was just the natural order of life. Once estrogen levels started to drop, the her-2 would become unchecked and relatively quickly, the 30-something female would simply expire. For a long time I looked at her-2 as a remnant of some sort of self - destruct mechanism, but now I am not so sure. Still, for me, I progress less actively when my own estrogen is not inhibited. I progress moreso when it is chemically inhibited..as I did at various times in 1997 and 1998 while taking very high doses of CAF and taxotere...which AS MANY OF US on this site "know" causes chemically induced menopause...naturally as I was so young back then...once the chemo stopped...everything just went back to normal..my periods are regular and mostly like clockwork ever since.

So although I realize I am THE ABSOLUTELY ONLY person in the world who finds estrogen with her-2 a very USEFUL combination..smile..I will just stop before the tomatoes start to be thrown at me...smile.

As far as to using herceptin differently from most folks, you have to understand that above all things I consider myself an independent thinker and do not bend easily to the opinions of others..nahhhhh...giggle...giggle....even though many times--in many areas of my life..not just cancer, I have had to pay a very high price for this free thinking, so when my first onc saw the liver spots and told me I would be dead in about 2 months and to find a family for my son to live with and put all my affairs in order...I had difficulty believing "HIS VERSION" of reality as I sat there holding a PERFECT blood chemistry in my hand...and apart from a severely inflamed liver that was causing me serious digestive difficulties, I felt--as strange as it is to say...that my general constitution was perfectly HEALTHY and some how in balance and my intuition told me that what I was fighting was a much more LOCALIZED event than the terms metastatic cancer tend to suggest...which really means, of course, systemic. So I had a real difficulty merging the reality of the "world view" of my onc with the reality of what my own body was telling me....I also had a REAL problem with the theory "that MY genes were all messed up and this is what was causing my cancer"...for many reasons, it just did not "seem" to me to be the case. Anyway, no one will understand what I am trying to express, but somehow, I just thought that something else -- an outside force, an external first cause-- was at work here and I worried that like Helen Longino's LANDMARK work, "Science as Social Knowledge" maybe the entire cancer paradigm was based on one or two terribly wrong first assumptions, and because we were all so embedded in the paradigm we just couldn't see it. So, like Ockham's razor, I decided, then and there, that I would do the best I could to wipe my mind clean of everything I had ever heard, read, learned or been told about all that it means to have cancer and I would start fresh, using my own life experience and my own blood work as my lab.

What I found was pretty much any thing we had be led to "believe" about cancer, did not hold up to empirical testing and measuring...with very little effort and very few resources, I found that I could pretty much find at least ONE FALSE example of every TRUISM ever taught about this hideous disease...to me, the empirical data and my own poignant reactions to my experiences and later from the detailed observations of others with her-2 and other cancers became my only truth. I pig-headedly and dogmatically began to follow a very simple and pragmatic path. If something "worked" and could be tested and measured and proven of benefit, I continued with it. If I tried something, no MATTER HOW FABULOUS it was "believed" to work against her-2 or cancer, if it brought me personally no benefit that could be measured, I didn't waste my time, energy, or money. If I tried something that outright made me worse or nearly killed me (this happened on occasion as you must remember I tested many things early on BLINDLY), well, I just simply didn't test them or use them again, this included saying NO to more typical "chemo" concoctions and combos that onc after onc would offer me again and again and again...sighh... as I said above, I told my first onc after the first rounds with chemo which only bought me about 5 months of remission that, "Even if I died, I would not follow that route again." WHY?? because...HELLO...obviously, it didn't work for me.

Herceptin, of course, offered a completely different mechanism of action, one that was much more complementary to my style and way of thinking. For me, personally, someone with a history of robust health and ultra - high energy levels with an equally active child to raise alone, the price chemo levied, was way too high...also remember, chemo today, is not at all like it was back in 1997...I understand today the dosing is lower and there are more 'drugs' to control the nasties...not sure that is a good thing, but it is what it is.

Besides, I was still young and optimistic. I had very much wanted a large family as I am crazy for kids and get along well with them as I am just an over-grown one myself... I could not bear parting with my reproductive capability and besides I told myself, even back then...just wait it out...they have already invented herceptin...surely the next "BIG" breakthrough will be long before my biological clock ticks its last tock..., but...I was wrong...I waited 6 years from November, 1998 when Herceptin was first approved by the FDA until late in 2004 it sadly began to dawn on me that I was turning 40 in that same year, and though happy that I was to be doing so, I realized that my clock was nearing its last tock and that for me, there not only would be no cure to arrive like a super hero in the nick of time to save the day, but worst of all no daughter to beget...something given my heritage and the importance of passing on my mitochondrial DNA that was very important to me...just another thing in a long line of so many, that having her-2 mediated disease had taken away from me. But worst of all, as bad as having this disease was for myself..., what I could not get off my mind was the horrors it was doing to others in my 'clan' others like me...perhaps, going way back...even others of my own blood. I often thought on that quote originally from Plato I believe about the sacrifice of the one for the many, but if you are already on the her-2 fast track to destination death, it becomes not a sacrifice, but merely the only path unbarred.

It is now 2006. In a few more days, I will turn 42. I am profoundly grateful at my nearly unprecedented her-2 longevity, but at the same time, dismayed that now even two MORE years have passed, and yet, I find myself still tethered to the exact same spot, dragging my Herceptin infusion behind me.

We can not keep waiting. We must come together and solve the puzzle for ourselves. If we wait for science, as a very wise man, Stu Kaufman, author of "At home in the Universe" and the key promoter of complexity theory and self-organization of matter once predicted, it could take another 20 years.

I have lost nearly a decade to this disease. I will not stand by silently for 2 more. There has to be a better way. There is and together we can find it.

OK..ok...more tomatoes..ooh and rotten eggs..smile...time to say goodnite,
Gina

Gina,
In a very fascinating article in The Economist they speculated that humans are the only species where the female survives substantially beyond reproductive age is due to the importance to the species of the contribution made by grandmothers--including freeing up their daughters to have more energy to produce more grandchildren.


I have not contributed to the species by being either a mother or a grandmother, so who am I to contribute to this topic further?

Enough tonight for evolutionary thinking!

The relationship between ER and her2 is still being discovered. A most interesting article hot off the press:

1: Mol Cell. 2006 Feb 3;21(3):393-404.
Links

Combinatorial Analysis of Transcription Factor Partners Reveals Recruitment of c-MYC to Estrogen Receptor-alpha Responsive Promoters.

Cheng AS, Jin VX, Fan M, Smith LT, Liyanarachchi S, Yan PS, Leu YW, Chan MW, Plass C, Nephew KP, Davuluri RV, Huang TH.

Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210.

In breast cancer and normal estrogen target tissues, estrogen receptor-alpha (ERalpha) signaling results in the establishment of spatiotemporal patterns of gene expression. Whereas primary target gene regulation by ERalpha involves recruitment of coregulatory proteins, coactivators, or corepressors, activation of these downstream promoters by receptor signaling may also involve partnership of ERalpha with other transcription factors. By using an integrated, genome-wide approach that involves ChIP-chip and computational modeling, we uncovered 13 ERalpha-responsive promoters containing both ERalpha and c-MYC binding elements located within close proximity (13-214 bp) to each other. Estrogen stimulation enhanced the c-MYC-ERalpha interaction and facilitated the association of ERalpha, c-MYC, and the coactivator TRRAP with these estrogen-responsive promoters, resulting in chromatin remodeling and increased transcription. These results suggest that ERalpha and c-MYC physically interact to stabilize the ERalpha-coactivator complex, thereby permitting other signal transduction pathways to fine-tune estrogen-mediated signaling networks.

PMID: 16455494 [PubMed - in process]

Lots still to unravel!

Lani,
Fascinating posts you have obviously been busy looking at the subject generally.

The whole subject of fats, BC, herceptin, insulin usage, diabetes, coronary and vascular health, all seem to have some common connections is this hugely complex puzzle.

My own definately non expert suggestion is that the omega three six balance is a magor factor, and that cutting down in omega six is key. I am not sure where oleic acid fits in, but the usage of quality olive oil instead of high omega six sources could be a factor as could any inherent properties of oleic sources.

I have only skimmed the above and will come back on it.

Both omega three and six are closely linked to the PPARs. I need to re-read the bits I have saved. Why a fraction of the funds that are put into the development of drugs could not be put into looking at dietary factors is my question. Did anybody see the reports that diabetes in Harlem is heading to an appearance in one person in five. PPAR is also mentioned in relation to diabetes.

As a start in relation to the post on PPAR gamma above here is a link on PPAR gamma. The article calls PPAR gamma "A MASTER REGULATOR OF THE FORMATION OF BODY FAT" .


http://www.salk.edu/news/releases/details.php?id=54

Salk Scientists Identify Molecular Link Between Dietary Fat And Colon Cancer

July 31, 1998
LA JOLLA, CA — Although it's now common wisdom that dietary fat is related to some cancers, medical researchers have not understood the underlying mechanisms. In research reported in the September 1 issue of Nature Medicine, scientists at The Salk Institute for Biological Studies identify a molecular link between fat metabolism and colon cancer. The results may also be relevant to breast and prostate cancer, common cancers that are also associated with dietary fat.

"The identification of a specific molecular fat sensor that contributes to human cancer provides us with a direct opportunity to develop new classes of pharmaceutical drugs," according to Salk Professor Ronald Evans, senior author of the study.

The link, a molecule named PPAR gamma, was shown in previous work from Evans' laboratory to aid in the formation of fat cells and storage of fat. In the current study, mice given compounds known to stimulate PPAR gamma developed three times as many colon polyps as their litter mates. The strain of mice used in the experiments are predisposed to develop colon polyps and are frequently used as a model for human familial colon cancer.

On the molecular level, PPAR gamma acts as a fat sensorÑhormones, drugs, and dietary fats attach to the sensor to exert their influence. Earlier work had shown that PPAR gamma and its hormone serve as a master regulator of the formation of body fat.

The current study used synthetic hormones to attach to PPAR gamma; mice given these hormones developed polyps at a rate comparable to mice in other studies that were maintained on high-fat diets.

"The results are highly suggestive of PPAR gamma mediating the connection between fat intake and cancer promotion," said Enrique Saez, postdoctoral fellow and lead author of the study. "Presumably fat stimulates PPAR gamma to regulate genes that control cell division, cell death or other aspects of tumor development. The next step is to identify these genetic targets."

Because PPAR gamma also is found in breast and prostate cancer cells, the investigators believe the current study has implications for understanding the link between dietary fat and these two common cancers.

In addition to their relevance to tumor development, the findings raise questions about medical treatments currently used for diabetes. Troglitazone, marketed as Rezulin and one of the most commonly prescribed drugs for non-insulin dependent diabetes, stimulates PPAR gamma and is the same hormone used by the Evans group.

"These findings raise the issue of whether troglitazone treatment might increase risk for colon cancer," according to Peter Tontonoz, M.D., postdoctoral fellow and a co-author of the study. "It's an issue that should be examined, particularly in patients with a family history of colon cancer."

He added that troglitazone treatment did not increase colon polyps in normal mice and therefore might not present a risk to diabetes patients with no family history of colorectal cancer.

Paradoxically, when the investigators treated colon cells in tissue culture with PPAR gamma stimulators, tumor cells actually lost some of their cancer-like properties and began to revert to normal. A research group from the Dana Farber Cancer Institute in Boston reports similar results with cultured cells in the same issue of Nature Medicine and advocates using PPAR gamma stimulators to treat colon cancers. "We're not sure why we should see this conflict between the in vitro and in vivo results," said Evans. "But we believe that the animal results are probably more relevant to what goes on in human beings and caution against using PPAR gamma stimulators in humans."

A third paper in the journal from a team at Institut Pasteur in Lille, France reports results in mice that agree with the Salk findings. Salk co-authors include research technicians Michael C. Nelson, Jacqueline G. A. Alvarez and Tze Ming U. Collaborators include Stephen M. Baird, M.D., a surgical pathologist at the University of California, San Diego; and Vilmos A. Thomazy, M.D., a pathologist at the University of Texas at Houston Medical School. Evans is a Howard Hughes Medical Institute investigator, and Saez was supported by the Susan G. Komen Breast Cancer Foundation.

The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution conducting basic science research dedicated to the improvement of human health and improving the quantity and quality of the world's food supply.

Its two main fields of concentration are neuroscience and molecular-cellular biology and genetics.
###

Another trial linking omega three, PPAR gamma, and BC.

RB


ABSTRACT

1: Br J Nutr. 2002 Mar;87(3):193-8. Related Articles, Links


N-3 fatty acids and lipid peroxidation in breast cancer inhibition.

Stoll BA.

Oncology Department, St Thomas' Hospital, London, UK.

Long-chain n-3 fatty acids (FA) consistently inhibit the growth of human breast cancer (BC) cells both in culture and in grafts in immunosuppressed mice. Large cohort studies have, however, failed to confirm a protective effect for fish oils rich in n-3 FA against BC risk. The present review examines new evidence on biological mechanisms which may be involved in the inhibition of mammary carcinogenesis by long-chain n-3 FA, focusing on an apoptotic effect by its lipid peroxidation products. Dietary intake of n-3 FA leads to their incorporation into cell membrane lipids. Increased apoptosis in human BC cells following exposure to long-chain n-3 FA such as eicosapentaenoic and docosahexaenoic acids is generally ascribed to their inhibition of cyclooxygenase 2 which promotes mammary carcinogenesis. In addition however, long-chain n-3 FA are particularly likely to activate peroxisome proliferator-activated receptor (PPAR)-gamma, a key regulator of lipid metabolism but also capable of modulating proliferative activity in a variety of cells including mammary cells. Expression of PPAR-gamma in the nucleus is activated by second messengers such as J series prostaglandins and the latter have been shown to cause apoptosis in vivo in explants of human BC cells in immunosuppressed mice. In mammary tumours, it is observed that long-chain FA not only increase apoptosis, but also increase lipid peroxidation, and the apoptotic effect can be reversed by antioxidants. The rationale for use of n-3 FA dietary supplements in counteracting BC progression needs to be tested clinically in a phase 2 pilot study, while at the same time, the effect on whole-body lipid peroxidation needs to be monitored. Dietary supplements of fish oil rich in n-3 FA are proposed for premenopausal women over the age of 40 years who are shown to be at increased BC risk. Biological markers in breast tissue of BC progression will be monitored, and observed changes related to serial plasma levels of isoprostanes as a measure of whole-body lipid peroxidation.

Publication Types:
• Review
• Review, Tutorial

PMID: 12064327 [PubMed - indexed for MEDLINE]

I too have looked for trials looking at the impact of omega threes on the efficacy of herceptin.

I have looked on NCIB and cannot find anything.

I have a nagging feeling I have seen somthing but cannot recall the details, or if it related to another treatment.

If I find it I will post it.

RB

[RobinP]

Gina, I find your post interesting as always. However, I disagree with you respectivefully on several points.

First, your theory on female ancestry with early death from declining female estrogen is novel and questionable in my mind. I agree with Lani's interpretation about the importance of ancient female extended life expectancy rather than early death from declining female estrogen.

Additionally, I believe what activates the her2 receptor is a hyperactive estrogen state, as opposed to a declining one. Once estrogen is over stimulated, it is scientifically known that the G cycle in cellular transcription is over activated. Once this occurs, her2 can be activated, eliminating estrogen as the driver to tumor growth. I doubt very much that menopause negatively impacts on her2 bc.

Nonetheless, I appreciate you sharing your personal experiences which are always interesting with your experience in living with advanced her2 bc. Additionally, I also welcome a difference in opinion. If we all thought the same here, what would be the use of our communication anyway? Take care Gina.

PS. I too feel cheated with breast cancer in many ways. Sorry you didn't get the daughter, you so desired.

[Gina]

is the freedom we all share to exchange ideas no matter how varied or outside the box they may be. It is only thanks to high level of trust and comfort that this board nurtures that enables many of us who would otherwise remain silent to actually speak up and sometimes, even speak out. We are so fortunate to have such a truly OPEN forum and I can not thank Christine and Joe enough for all they must do behind- the- scenes to continually provide us with such a fabulous tool.

Obviously, many of us will differ in ideology from time to time, and I admittedly tend to follow evolutionary thinking and enjoy reading folks like Darwin, Richard Dawson and Bryan Skyes and many others who share these views. However, I also read Stu Kaufman (At home in the Universe, is particularly accessible) and several varied supporters of intelligent design and was personally raised very strictly religious and protestant.

That said, almost any anthropology book that you would pick up would note that the lives of the early hominids were brief, certainly by 21st century homo sapien standards anyway...and "grandmothers" actually are a rather recent evolutionary phenomenon, one that has MOST likely--as was pointed out above, made a world of difference to our entire culture.

I will look up the studies on the inverse relationship between estrogen and her-2 and post them either here or in the articles section for any one interested...the her-2 link to a common ancestor ideas presented in my thread above were just some original research areas that if I had the time, I would enjoy pursuing..more as a hobby than serious "science"...smile... Also, it is important to remember that her-2, as a remnant of some sort of self-destruct mechanism, was an early theory that I examined and not one that I pay much attention to these days, but is still viable until proved or disproved one way or the other.

However, it is at least of passing note that a LARGE percentage of species, extinct and contemporary, die out after their reproductive capabilities have diminished in order to free up and provide space and resources so that their young might flourish. Our species found, however, ...over many, many years of evolution, that the emergence of "grandmothers" provided both significant survival advantage to our progeny and a reliable way to increase our numbers "to cover all the earth"...and this is just as true today as it was perhaps, thousands of years ago...grandmothers are a very vital link to all that we were in the past and to much of what our sons and daughters will become in the next generations.

Grandmothers to mothers to daughters pass on the mitochondrial DNA..., latest research areas of interest has been to zero- in on this mitochondrial DNA to see if it has any involvement with the her-2 cascade scenarios. And even though I tend to follow an infectuous first cause paradigm of her-2, I can not ignore the data that not only do quinolones and other certain types of antibiotics disrupt plasmid protein synthesis, but they ALSO, by virtue of the fact that the mitochondria were-- in pre-eucaryote days anyway, most likely bacteria, ..have the power to disrupt mitochondrial DNA/ RNA protein synthesis and if some part of the A to c-myc- to her-2 to Vegf to Z cascade is being influenced by these mitochondrial pathways--passed down to us from those very same great great great grandmothers, then, the disruption caused by the quinolones and other certain classes of antibiotics is what produces the positive effect in downgrading her-2 mediated disease and not because these quinolones and other antibiotics are taking out some postulated first cause air breathing gram negative organism...but, if one were to strictly apply Ockham's razor here...the infectuous first cause theory would still win out as it is the most elegant by virtue of its simplicity of the two: Take out the organism causing the cascade and entire cancer promoting machinery grinds to a dead stop, and the rest of the cell is left intact.

Pragmatism would urge us not to waste time debating the two theories as ad hoc though they may be--as the end result is more or less the same, but if, for whatever reasons the quinolones and certain anti-biotics have a measureable effect on down grading her-2, let's release that for compassionate use RIGHT now and save the splitting -hair arguments for why they work for later, but that is just me, someone who supports a common sense to science approach.

In order to ever do justice to investigating ANY of these outside -the -box original hypotheses, one would certainly require more resources than a private citizen such as myself has at this time anyway. Also, love him or hate him, even our President --in his recent State of the Union speech --was calling on PRIVATE as well as public sector involvement to get on board, regardless of partisan politics, and simply SOLVE THE PROBLEMS. The new Virginia Governor, echoed this exact same sentiment in his after remarks and is well-known to have worked hard in Virginia with former governor Mark Warner to achieve just that.

Folks, we have a multi-faceted problem here were her-2 is concerned. If proteins were bits of colored yarn..it is like we have a multi-colored, knotted wad of them to untangle before completely understanding the mechanism of her-2 mediated disease.

Let's start untying the knots and unraveling the yarn....the more of us who share what we are learning with each other on this board, just like we have been doing in this thread and so many others, the faster we can unravel the whole ball. Let's agree that not only is it OK to disagree, but that it is expected and even sought after. Nothing new and different is-- by definition-- ever created out of absolute homogeneity. Only after debating and reviewing as many angles of the issue and viewpoints as we can will the taste of ultimate consensus be obtained and made all the sweeter. I look forward to that day.

Also, on the issue of begetting and the expanded value of web-sites such as ours, I was thinking today, that in the past, the only way the DNA could be passed on was via physical direct transmission from one generation to the next and unless you passed your genes on via this route, they died with you. But then, it occurred to me that thanks to the invention of the internet, for those of us who may not be blessed to pass on our "code" in the traditional way, that sites such as these may evolve into collective knowledge repositories that in their own way will transmit "the code" of life via wisdom gained and transmitted by words rather than merely genes to future generations and that these repositories will benefit and advance our species continued survival and expansion in a way not unlike the extended benefit provided by our grandmothers. So in the final analysis, even though I may never physically be able to transmit my own mitochondrial DNA to an actual "daughter" there still remains hope that something of what my great, great, great, grandmothers passed down to me, may still live on, not in the flesh, but in the word.

"In the beginning was the word."

Godspeed,
Gina

[Becky]

There are theories that the mitochondrial DNA (which is vastly different than the DNA in our cells) was incorporated via a bacteria or other organism (God knows when). This happened as a positive symbiotic relationship as the mitochondria is the powerhouse work station within a cell (the site where glucose is broken down into ATP - the essence of the energy of life). Mitochondrial DNA is simple versus that of our cells. So simple that the bacteria incorporation theory was formulated.


Think of the mitochondria as the powerplant of the cell but it sings its own song versus all the cells in your body that sing a different song. However, heart cells sing a different part of that song than a lung cell than a skin cell (but it is still the same song while the mitochondrial song is entirely different in every way).

That's all for now

Becky

[RobinP]

Gina, interesting explanations on why declining estrogen stimulates her2. However, wouldn't you say that just before menopause, one often has imbalanced menstrual cycles with increased estrogen levels as well as decreased estrogen levels?

If you want to state that her2 is some evolutionary mechanism for death, then I would maintain that increased estrogen is what is turning that mechanism on, not decreased estrogen levels. Also, please explain to me why so many young people have her2+ bc as opposed to older women if declining estrogen levels causes her2 stimulation.

Gina, would you ever consider HRT when you become menopausal with natural estradiol and progesterone since you are so concerned about declining estrogen stimuating her2?

I have no idea how it all sits together, but the more one sees the more it is evident it all interlinks somehow and proably explains why herceptin acts also on coronary health, and for me a very personal view underlines the importance of at the least balancing the omega threes and sixes.

You will see linoleic acid features again.

RB

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum


1: J Biol Chem. 2005 Oct 14;280(41):34786-95. Epub 2005 Aug 10. Related Articles, Links
Click here to read
Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements.

Armoni M, Harel C, Bar-Yoseph F, Milo S, Karnieli E.

Institute of Endocrinology, Diabetes and Metabolism, Rambam Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.

Hyperlipidemia (HL) impairs cardiac glucose homeostasis, but the molecular mechanisms involved are yet unclear. We examined HL-regulated GLUT4 and peroxisome proliferator-activated receptor (PPAR) gamma gene expression in human cardiac muscle. Compared with control patients, GLUT4 protein levels were 30% lower in human cardiac muscle biopsies from patients with HL and/or type 2 diabetes mellitus, whereas GLUT4 mRNA levels were unchanged. PPARgamma mRNA levels were 30-50% lower in patients with HL and/or diabetes mellitus type 2 than in controls. Reporter studies in H9C2 cardiomyotubes showed that HL in vitro, induced by high levels of arachidonic (AA) stearic, linoleic, and oleic acids (24 h, 200 mum) repressed transcription from the GLUT4 promoter; AA also repressed transcription from the PPARgamma1 and PPARgamma2 promoters. Co-expression of PPARgamma2 repressed GLUT4 promoter activity, and the addition of AA further enhanced this effect. 5'-Deletion analysis revealed three GLUT4 promoter regions that accounted for AA-mediated effects: two repression-mediating sequences at -443/-423 bp and -222/-197 bp, the deletion of either or both of which led to a partial derepression of promoter activity, and a third derepression-mediating sequence at -612/-587 bp that was required for sustaining this derepression effect. Electromobility shift assay further shows that AA enhanced binding to two of the three regions of cardiac nuclear protein(s), the nature of which is still unknown. We propose that HL, exhibited as a high free fatty acid level, modulates GLUT4 gene expression in cardiac muscle via a complex mechanism that includes: (a) binding of AA mediator proteins to three newly identified response elements on the GLUT4 promoter gene and (b) repression of GLUT4 and the PPARgamma genes by AA.

PMID: 16096283 [PubMed - indexed for MEDLINE]

Re the evolutionary theory.

I cannot comment on the impact of declining or increasing eostrogen, but I have seen articles suggesting that cancers are in part a reflection of an evolutionary response, a triggering of elemental cells in reponse to environmental stress (of all sorts including diet), and I would guess oestrogen is in there somewhere. The more I read on oestrogen the more complex it appears given the bodies ability to produce it in different ways at different sites, to store it etc. I think the trials / suggestions that in certain limited circumstances that eostrogen can work against BC, might indicate it is all a great deal more complex than we yet realise, and todays absolute views on eostrogen exclusion might become rather less absolute in the future - as to the relative merits of your discussion I simply have not read do not know enough to comment specifically.

My personal strictly amateur guess at a significant trigger is the huge excess of omega six intake, over historic levels compunded by low omega threes, trans fats, and exclusion of small amounts of traditional sources such as dairy. It is a clearly evident trend. The impact of grossly stoking the omega six emergency repair inflamatory pathways are also evident in many other related diseases, coronary, diabetes, arthritis. Fats are truly fundamental to life.

That is not to say it expalins all or is the only factor, but my hunch is it is a magor one.

RB

Another interesting trial linking ppars to fats insulin etc.

RB

ABSTRACT

1: Endocrinology. 2005 Aug;146(8):3266-76. Epub 2005 May 5. Related Articles, Links
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* Endocrinology. 2005 Aug;146(8):3263-5.


Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPARgamma attenuates, glucose-stimulated insulin secretion in pancreatic beta-cells.

Ravnskjaer K, Boergesen M, Rubi B, Larsen JK, Nielsen T, Fridriksson J, Maechler P, Mandrup S.

Department of Biochemistry and Molecular Biology University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.

Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic beta-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of beta-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARalpha and retinoid X receptor alpha (RXRalpha) in INS-1E beta-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARalpha target genes and enhances FA uptake and beta-oxidation. In contrast, ectopic expression of PPARgamma/RXRalpha increases FA uptake and deposition as triacylglycerides. Although the expression of PPARalpha/RXRalpha leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARgamma/RXRalpha attenuates GSIS, the expression of PPARalpha/RXRalpha potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes alpha and gamma on lipid partitioning and insulin secretion when systematically compared in a beta-cell context.

PMID: 15878969 [PubMed - indexed for MEDLINE]

I have a headache from all this info-- and it's not from the herceptin
Carol

I have a headache from all this info-- and it's not from the herceptin
Carol

[Barbara H.]

Hi Gina and others.
I have read all the posts with great interest. I especially was moved by your since of passing down your thoughts or wisdom, Gina. These ideas are certainly in the literature.
Tennyson:
" Far on the ringing plains of windy Troy.
I am a part of all that I have met;
Yet all experience is an arch wherethro’
Gleams that untravell’d world whose margin fades
For ever and forever when I move"
Best wishes,
Barbara H.

Sorry about repeating myself--- some kind of slip
Carol

[julierene]

This is going to sound crazy, but Gina's response bothered me for a LONG time and I couldn't figure out why.... After a lot more research, I think it finally hit me. So I went and found the topic again, and thought I would ask you guys.

I hope I don't offend Gina, she's a smart cookie! She has a long theory about Herceptin Ineffectiveness, and I was thinking:

1) Haven't the studies shown that MORE Herceptin gives the same results as the current dosages without increasing effectiveness?

2) Why not make the theory that the tumor cells have capabilities of "learning"? I used the term loosely though, because I don't think cancer cells are necessarily smart - but maybe just survive out of 'natural selection'.


Cancer isn't just one type of cell replicating itself over and over. It's a product of an immune system that fails to recognize a damaged cell. My left breast had er-/pr- grade 3, IDC. My right breast had er+/pr- moderately differentiated DCIS. When I found out about that, I was like how? How could I be er-/pr- in one breast and er+/pr- in the other? It wasn't about the cancer... It was about my immune systems inability to recognize bad cells. Our normal cells are constantly learning how to overcome viruses and all sorts of stuff. The immune system seems smart when it comes to foreign attack (in a lot of cases). But when it comes to our own body malfunction, it struggles - especially when our genetics aren't perfect.

We already know that cells have a LOT of receptors on their surface. HER2/neu is just one of them. But for those of us who are HER2+++, that's great right? Think about this made up example for a minute:

I would think Herceptin Ineffectiveness is a mechanism where those tumor cells (in their active state) whose cell surface makeup has a few more IGF-IR receptors, survive and replicate after Herceptin has blocked all of the HER2 receptors on its surface. Even though the HER2 receptors are plugged, the immune system doesn't necessarily kill the cell. For many of us, the chemotherapy is what goes in and kills all the fast dividing cells. Just because the receptors are blocked, doesn't mean the cell is dead.

Those cells that have almost all HER2 receptors are killed (while in their active state), because chemo comes in and recognizes it as a fast dividing cell. While on Herceptin alone, the stuff that's maybe got some IGF-IR receptors - could live (if not in their active state, maybe while in their inactive state. I am on the side of the fence of oncology theory that believe cancer cells 'hide' while in their stem cell slowly dividing state - which is why they evade chemotherapy). As those cells live, I think more are replicated with 'possibly' more of those type of IGF-IR receptors. As all the HER2 receptors start to disappear (because those cancer cells were killed - either because they had no receptors left or the chemo killed them) - we get cancer cells that continue to divide - even while taking Herceptin. <Maybe the HER2/neu receptors are being blocked, but the IGF-IR unblocked receptors allow the cell to survive and divide?>

Is it plausible?

<I used IGF-IR just because it's a hot topic and I can't remember all the other ones abbreviations>

I have been re-reading this thread and find it so interesting. I am not ER/PR- but the concept that declining hormone levels could feed the cancer...that is to say....somehow it helps to be young and pre-menstral just rang a little bell...lol. There is a actress from Threes Company would had breast cancer and has written books about and talks about increasing your hormone levels. Every time I hear references to her in this regard I sort of shake my head as it flying in the face of what I have been taught about breast cancer but perhaps she has some good ideas for you hormone negative gals??

Cathya

[Cathya]

I just remembered her name.....Suzanne Summers.

Cathya