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

Since herceptin reportedly only works in 30% of 'appropriately targetted' her2 positive patients and as those in whom it does work in can become resistant with time, perhaps adding one of these two drugs to the regimen (even early on) could help it be more effective or stave off resistance:

1: Int J Cancer. 2006 Jan 19; [Epub ahead of print] Links

Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone.

Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. (c) 2006 Wiley-Liss, Inc.

PMID: 16425225 [PubMed - as supplied by publisher]

I frequently read articles stating that herceptin reportedly only works in 30%-35% of appropriately targeted her2 positive patients and that the majority of the patients it does work in can become resistant with time. Perhaps the former is because they were not testing her2 properly as recent articles have reported as high as 72% complete pathologic response when combining docetaxel and Herceptin as neoadjuvant therapy in Stage II and III patients.

In any case, since activation and increased expression of PTEN supposedly has much to do with herceptin efficacy, perhaps adding one of the following two drugs to the regimen (even early on) could help it be more effective or stave off resistance--lovastatin is an anticholesterol drug, rosiglitazone is an antidiabetes(type2)drug. Since IGFR1 signalling cross-talk is also felt to be a factor in herceptin resistance, perhaps Robin P’s admonition to keep exercising is all the more pertinent! Articles about the role of Vitamin D, omega 3s, orlistat, etc usually just state they are more than additive in their effect when combines with herceptin on breast cancer CELL LINES in vitro--found any articles which would imply that they would make herceptin more likely to be effective in an individual or decrease the likelihood of the development of resistance? Any and all thoughts appreciated!

1: Int J Cancer. 2006 Jan 19; [Epub ahead of print] Links

Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone.

Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. (c) 2006 Wiley-Liss, Inc.

PMID: 16425225 [PubMed - as supplied by publisher]

*-35%
1: Br J Cancer. 2006 Jan 10; [Epub ahead of print]
Related Articles, Links
*
PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer.

Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, Tsukuda K, Ogasawara Y, Shimizu N.

1Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, 700-8558 Okayama, Japan.

Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.British Journal of Cancer advance online publication, 10 January 2006; doi:10.1038/sj.bjc.6602926 www.bjcancer.com.

PMID: 16404430 [PubMed - as supplied by publisher]

: Mol Cancer Ther. 2002 Jul;1(9):707-17.
Related Articles, Links
*
Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.

Clark AS, West K, Streicher S, Dennis PA.

Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.

To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies.

PMID: 12479367 [PubMed - indexed for MEDLINE]



1: Int J Cancer. 2005 Sep 1;116(3):359-67.
Related Articles, Links
*
Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2.

Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH.

Institute of Pathology, The University of Oslo, Rikshospitalet, Oslo, Norway.

The anti-proliferative effect of the ErbB2 specific antibody Herceptin in cells overexpressing ErbB2 has previously been explained by endocytic downregulation of ErbB2. However, in the following, we demonstrate that Herceptin inhibited proliferation of ErbB2 overexpressing cells without downregulating ErbB2. Herceptin did also not induce endocytosis of ErbB2. Herceptin was found to blunt proliferation of SKBr3 cells overexpressing EGFR, ErbB2, and ErbB3 and expressing functional PTEN, probably by recruiting PTEN to the plasma membrane. Akt was found to be constitutively phosphorylated both in SKBr3 cells overexpressing EGFR, ErbB2 and ErbB3, and in SKOv3 cells, overexpressing EGFR and ErbB2. However, phosphorylation of Akt was inhibited by Herceptin only in SKBr3 cells. SKOv3 cells, which lack the tumour suppressor protein Ras homolog member I, was found to have constitutively phosphorylated mitogen activated protein kinase and functionally increased Ras activity. SKOv3 cells further had low expression levels of PTEN. We thus confirm that the anti-proliferative effect of Herceptin in SKBr3 cells is due to recruitment of PTEN to the plasma membrane and conclude that Herceptin does not blunt phosphatidyl inositol 3 kinase-induced growth in cells with constitutive Ras activity. We further conclude that endocytic downregulation of ErbB2 does not contribute to Herceptin's antiproliferative effect.

PMID: 15800944 [PubMed - indexed for MEDLINE]

1: Cancer Cell. 2004 Aug;6(2):117-27.
Related Articles, Links
*
Comment in:
• Cancer Cell. 2004 Aug;6(2):103-4.

PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D.

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

The ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.

PMID: 15324695 [PubMed - indexed for MEDLINE]

: Mol Cancer Ther. 2002 Jul;1(9):707-17.
Related Articles, Links
*
Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.

Clark AS, West K, Streicher S, Dennis PA.

Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.

To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies.

PMID: 12479367 [PubMed - indexed for MEDLINE]

: Cancer Res. 2005 Dec 1;65(23):11118-28. Related Articles, Links

Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells.

Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ.

Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.

The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and HER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti-IGF-IR antibody alpha-IR3 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by alpha-IR3 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither alpha-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.

PMID: 16322262 [PubMed - in process]

They also said her2+er+ tumors only made up 10% of her2+tumors for years and years until this year when the centralized/better testing required for the Herceptin trials in No. America and HERA trials came back with a figure more like 45%. And remember, herceptin research was almost given up because it was hardly more effective than control (because the patients they tried it on where not appropriately selected and/or inadequate/erroneous her2 testing had been carried out). As the mechanism(s) of action of herceptin are better understood, and her2testing improves and/or more reproducible/central testing is carried out, these statistics should probably improve. It is only with continued use of herceptin that we will see if/how often herceptin resistance occurs, whether it can be reversed by available/or soon to be available agents (lapatinib)and who it occurs in. Many on this site it seems have been on Herceptin for 6-8 years without loss of efficacy.

That said, any reports of ways which might relatively easily (and with few side effects) improve the chances of Herceptin function--flaxseed oil, primrose oil, even perhaps Xenical--are certainly welcome!

Sorry to have been so verbose this morning. I held this post for three days
while deciding whether its positive implications outweighed any negative thoughts it might entertain.

Hope this helps!
Lani

[Julie2]

I really want to persue the 2nd year of adjuvant Herceptin as my first year is coming to an end in Feb 06. But I am hesitating so much in fear of developing resistance to it as mentioned in the above article. Anybody has any thoughts?

Julie

In the metastatic setting, they have found if tumors recur/progress on Herceptin it is usually best to keep the patient on herceptin and add something to it. So herceptin "resistance" may be a bad term. It still works, it is just the cancer may have found other ways to multiply that need to be blocked as well. It is like a puppy in the house--you may have blocked the front door, but it will eventually explore and found other doors to get out into the yard and chase that squirrel! It doesn't mean you should leave the front door open, only that you need to close more doors.

Hope this helps!
Lani

[al from Canada]

Hey Lani,

I think you are on the right track. I have to apologize and admit that I only skimmed the abstracts as I'm very tight on time these days due to Linda's tx.

Most of the stuff in the articles talks about the down-regulation of HER2.
Let me postulate 4 scenarios:

1. Let's assume herceptin is working but not optimally; I agree that you can downregulate HER2 say with oleic acids therefore weakening the HER2 receptors thus increasing suseptability to herceptin

2. The HER2/AKT/PI3K.....by down-regulating PI3K and upregulating PTEN which sensitizes the HER2 tumor cells to apoptosis.

3. Transciption: the dimerization of HER2 and EGFR (HER1) of HER3. In this case adding lapatinib or pertuzumab would be effective preventing transcription.

4. herceptin resistance: like any drug, herceptin will cause cells to develop resistance or habituate to the drug. It has been shown that herceptin resistant HER2 tumor cells can be re-sensitized to herceptin by adding an EGFR inhibitor such as lapatinib, iressa, centuximan or tarceva.

Here's my take: do molecular profiling on the tumor cells and target the therapy accordingly, (this doesn't sound like rocket science), ie. test for HER1 - 3, VEGF, PI3K, PTEN, ER, or........lets do a trial on active mets with herceptin + pertuzumab + avastin + lucentis (which attacks VEGF in a different way) + LY294002 + say a friendly chemo drug like Xeloda. If I personally, had stage 4 cancer; I would volunteer as what's the worst that will happen, I'll die young?? After that, maintainence with herceptin + lapatinib + Avastin (+ faslodex if ER+).

Diclaimer: don't believe me because I'm only a care-giver.

Al

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

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
Click here to read
Comment in:

* 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]