HER2 Support Group Forums - View Single Post

R.B. · 07-08-2006, 04:41 AM

There are many lacks in my knowledge so this is a bit of a guess from a half fhinished jigsaw but food for thought, and one for discussion with your onc.

Omega three has been shown to downregulate BC.

FAS part of the system the body uses to make fats is one of the pathways used by herceptin. (see below)

IF the body is dupplied with adequate levels of long chain DHA EPA etc fats in diet it stops making them, and so must be not using switching of FAS in some way. (lots of trials on NCBI)

The olive oil trial would suggest that the herceptin mechanisms are sensitive to fats intake. (see below)

Fish oils contain high levels 18:1 monsaturates (although it does not specify which) so the chances are that you may by taking fish oil (see analysys below);

1. Moderate fas pathways

2. Get the benifits ascribed to fish oil in BC

3. Cut down body inflamation

4. Get benifits from the 18:1s

5. Improve your nutrition

IT IS ESSENTIAL TO CUT RIGHT DOWN ON OMEGA SIX.

In terms of intravenous provision they use it for the very ill with benificial effects, but if your digestion is poor it might be a way of ensuring you are getting long chain threes into your system. Form the trial take up is better than from taking from diet.

I am only a dest top jockey so definately stuff for discussion with medical advisors.

Suggested optimal intake of DHA in a trail was two grams DHA a day which is about 5tps of a quality fish oil. I take double that plus at the moment. There are few reported side effects but blood thining is one and again you must consult with your advisors. DHA is a component of fish oil - check the label.

Trials suggest that the body's stored six can reduce the effect of intake of threes and hence my decision to take a higher level for a while.

Fish oil also help with irratable bowel etc., which is another inflamation based condition. (an interest of mine and it has improved significantly - balancing the threes and sixes is the biggest dietary change I have made)

Vitacost

http://www.vitacost.com/?csrc=SITEREF-linkshare

do a quality reasonably priced cod liver oil with no backtaste. Again I have no connection with the company except as a customer.

RB

http://www.nutritiondata.com/facts-B00001-01c20AC.html

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

1: Ann Oncol. 2005 Mar;16(3):359-71. Epub 2005 Jan 10. Related Articles, Links
Click here to read
Comment in:

* Ann Oncol. 2005 Mar;16(3):339-40.

Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification.

Menendez JA, Vellon L, Colomer R, Lupu R.

Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, USA.

BACKGROUND: The relationship between the intake of olive oil, the richest dietary source of the monounsaturated fatty acid oleic acid (OA; 18:1n-9), and breast cancer risk and progression has become a controversial issue. Moreover, it has been suggested that the protective effects of olive oil against breast cancer may be due to some other components of the oil rather than to a direct effect of OA. METHODS: Using flow cytometry, western blotting, immunofluorescence microscopy, metabolic status (MTT), soft-agar colony formation, enzymatic in situ labeling of apoptosis-induced DNA double-strand breaks (TUNEL assay analyses), and caspase-3-dependent poly-ADP ribose polymerase (PARP) cleavage assays, we characterized the effects of exogenous supplementation with OA on the expression of Her-2/neu oncogene, which plays an active role in breast cancer etiology and progression. In addition, we investigated the effects of OA on the efficacy of trastuzumab (Herceptin), a humanized monoclonal antibody binding with high affinity to the ectodomain of the Her-2/neu-coded p185(Her-2/neu) oncoprotein. To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the Her-2/neu oncogene. RESULTS: Flow cytometric analyses demonstrated a dramatic (up to 46%) reduction of cell surface-associated p185(Her-2/neu) following treatment of the Her-2/neu-overexpressors BT-474 and SK-Br3 with OA. Indeed, this effect was comparable to that found following exposure to optimal concentrations of trastuzumab (up to 48% reduction with 20 microg/ml trastuzumab). Remarkably, the concurrent exposure to OA and suboptimal concentrations of trastuzumab (5 microg/ml) synergistically down-regulated Her-2/neu expression, as determined by flow cytometry (up to 70% reduction), immunoblotting, and immunofluorescence microscopy studies. The nature of the cytotoxic interaction between OA and trastuzumab revealed a strong synergism, as assessed by MTT-based cell viability and anchorage-independent soft-agar colony formation assays. Moreover, OA co-exposure synergistically enhanced trastuzumab efficacy towards Her-2/neu overexpressors by promoting DNA fragmentation associated with apoptotic cell death, as confirmed by TUNEL and caspase-3-dependent PARP cleavage. In addition, treatment with OA and trastuzumab dramatically increased both the expression and the nuclear accumulation of p27(Kip1), a cyclin-dependent kinase inhibitor playing a key role in the onset and progression of Her-2/neu-related breast cancer. Finally, OA co-exposure significantly enhanced the ability of trastuzumab to inhibit signaling pathways downstream of Her-2/neu, including phosphoproteins such as AKT and MAPK. CONCLUSIONS: These findings demonstrate that OA, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu overexpression, which, in turn, interacts synergistically with anti-Her-2/neu immunotherapy by promoting apoptotic cell death of breast cancer cells with Her-2/neu oncogene amplification. This previously unrecognized property of OA offers a novel molecular mechanism by which individual fatty acids may regulate the malignant behavior of breast cancer cells and therefore be helpful in the design of future epidemiological studies and, eventually, dietary counseling.

PMID: 15642702 [PubMed - indexed for MEDLINE]

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

1: Med Hypotheses. 2005;64(5):997-1001. Related Articles, Links
Click here to read
Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells.

Menendez JA, Vellon L, Lupu R.

Department of Medicine, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, USA. javiermenendez72@yahoo.com

Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. Therefore, the identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Recent studies in breast cancer cells have revealed a bi-directional connection between Her-2/neu and fatty acid synthase (FAS), a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids from the 2-carbon donors malonyl-CoA and acetyl-CoA. Her-2/neu overexpression stimulates the FAS promoter and ultimately mediates increased endogenous fatty synthesis, and this Her-2/neu-mediated induction of breast cancer-associated FAS is inhibitable by trastuzumab. On the other hand, chemical FAS inhibitors as well as RNA interference-mediated silencing of FAS gene repress Her-2/neu gene expression at the transcriptional level. Moreover, specific FAS blockade synergistically sensitizes breast cancer cells carrying Her-2/neu-oncogene amplification and/or overexpression to trastuzumab-induced cell growth inhibition and apoptotic cell death. Strikingly, FAS inhibition synergistically interacts with trastuzumab in Her-2/neu-negative breast cancer cells engineered to overexpress Her-2/neu, thus suggesting that the molecular linkage between FAS activity and functioning of Her-2/neu cannot be explained only on the basis of a transcriptional repression of Her-2/neu gene promoter. Interestingly, while in liver and adipose tissue FAS produces fat from excess carbon consumed as carbohydrates, which is ultimately stored as triglycerides, in epithelial cancer cells, FAS activity is mainly involved in the production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), which point to an active role of FAS in the deregulation of membrane functioning in tumor cells. Importantly, clusters of Her-2/neu and EGFR (erbB-1) co-localize with lipid rafts and the lipid environment in the cell membrane of breast cancer cells profoundly influences their association properties and biological functions. We hypothesize that pharmacological or small interference RNA-induced inhibition of breast cancer-associated FAS will result in major changes in the synthesis of phospholipids which, in turn, should impair a correct cellular localization of Her-2/neu at the cellular membrane of breast cancer cells. In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas.

PMID: 15780499 [PubMed - indexed for MEDLINE]

07-08-2006, 04:41 AM	#10
R.B. Senior Member Join Date: Mar 2006 Posts: 1,843	There are many lacks in my knowledge so this is a bit of a guess from a half fhinished jigsaw but food for thought, and one for discussion with your onc. Omega three has been shown to downregulate BC. FAS part of the system the body uses to make fats is one of the pathways used by herceptin. (see below) IF the body is dupplied with adequate levels of long chain DHA EPA etc fats in diet it stops making them, and so must be not using switching of FAS in some way. (lots of trials on NCBI) The olive oil trial would suggest that the herceptin mechanisms are sensitive to fats intake. (see below) Fish oils contain high levels 18:1 monsaturates (although it does not specify which) so the chances are that you may by taking fish oil (see analysys below); 1. Moderate fas pathways 2. Get the benifits ascribed to fish oil in BC 3. Cut down body inflamation 4. Get benifits from the 18:1s 5. Improve your nutrition IT IS ESSENTIAL TO CUT RIGHT DOWN ON OMEGA SIX. In terms of intravenous provision they use it for the very ill with benificial effects, but if your digestion is poor it might be a way of ensuring you are getting long chain threes into your system. Form the trial take up is better than from taking from diet. I am only a dest top jockey so definately stuff for discussion with medical advisors. Suggested optimal intake of DHA in a trail was two grams DHA a day which is about 5tps of a quality fish oil. I take double that plus at the moment. There are few reported side effects but blood thining is one and again you must consult with your advisors. DHA is a component of fish oil - check the label. Trials suggest that the body's stored six can reduce the effect of intake of threes and hence my decision to take a higher level for a while. Fish oil also help with irratable bowel etc., which is another inflamation based condition. (an interest of mine and it has improved significantly - balancing the threes and sixes is the biggest dietary change I have made) Vitacost http://www.vitacost.com/?csrc=SITEREF-linkshare do a quality reasonably priced cod liver oil with no backtaste. Again I have no connection with the company except as a customer. RB http://www.nutritiondata.com/facts-B00001-01c20AC.html http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum 1: Ann Oncol. 2005 Mar;16(3):359-71. Epub 2005 Jan 10. Related Articles, Links Click here to read Comment in: * Ann Oncol. 2005 Mar;16(3):339-40. Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification. Menendez JA, Vellon L, Colomer R, Lupu R. Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, USA. BACKGROUND: The relationship between the intake of olive oil, the richest dietary source of the monounsaturated fatty acid oleic acid (OA; 18:1n-9), and breast cancer risk and progression has become a controversial issue. Moreover, it has been suggested that the protective effects of olive oil against breast cancer may be due to some other components of the oil rather than to a direct effect of OA. METHODS: Using flow cytometry, western blotting, immunofluorescence microscopy, metabolic status (MTT), soft-agar colony formation, enzymatic in situ labeling of apoptosis-induced DNA double-strand breaks (TUNEL assay analyses), and caspase-3-dependent poly-ADP ribose polymerase (PARP) cleavage assays, we characterized the effects of exogenous supplementation with OA on the expression of Her-2/neu oncogene, which plays an active role in breast cancer etiology and progression. In addition, we investigated the effects of OA on the efficacy of trastuzumab (Herceptin), a humanized monoclonal antibody binding with high affinity to the ectodomain of the Her-2/neu-coded p185(Her-2/neu) oncoprotein. To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the Her-2/neu oncogene. RESULTS: Flow cytometric analyses demonstrated a dramatic (up to 46%) reduction of cell surface-associated p185(Her-2/neu) following treatment of the Her-2/neu-overexpressors BT-474 and SK-Br3 with OA. Indeed, this effect was comparable to that found following exposure to optimal concentrations of trastuzumab (up to 48% reduction with 20 microg/ml trastuzumab). Remarkably, the concurrent exposure to OA and suboptimal concentrations of trastuzumab (5 microg/ml) synergistically down-regulated Her-2/neu expression, as determined by flow cytometry (up to 70% reduction), immunoblotting, and immunofluorescence microscopy studies. The nature of the cytotoxic interaction between OA and trastuzumab revealed a strong synergism, as assessed by MTT-based cell viability and anchorage-independent soft-agar colony formation assays. Moreover, OA co-exposure synergistically enhanced trastuzumab efficacy towards Her-2/neu overexpressors by promoting DNA fragmentation associated with apoptotic cell death, as confirmed by TUNEL and caspase-3-dependent PARP cleavage. In addition, treatment with OA and trastuzumab dramatically increased both the expression and the nuclear accumulation of p27(Kip1), a cyclin-dependent kinase inhibitor playing a key role in the onset and progression of Her-2/neu-related breast cancer. Finally, OA co-exposure significantly enhanced the ability of trastuzumab to inhibit signaling pathways downstream of Her-2/neu, including phosphoproteins such as AKT and MAPK. CONCLUSIONS: These findings demonstrate that OA, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu overexpression, which, in turn, interacts synergistically with anti-Her-2/neu immunotherapy by promoting apoptotic cell death of breast cancer cells with Her-2/neu oncogene amplification. This previously unrecognized property of OA offers a novel molecular mechanism by which individual fatty acids may regulate the malignant behavior of breast cancer cells and therefore be helpful in the design of future epidemiological studies and, eventually, dietary counseling. PMID: 15642702 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum 1: Med Hypotheses. 2005;64(5):997-1001. Related Articles, Links Click here to read Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. Menendez JA, Vellon L, Lupu R. Department of Medicine, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, USA. javiermenendez72@yahoo.com Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. Therefore, the identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Recent studies in breast cancer cells have revealed a bi-directional connection between Her-2/neu and fatty acid synthase (FAS), a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids from the 2-carbon donors malonyl-CoA and acetyl-CoA. Her-2/neu overexpression stimulates the FAS promoter and ultimately mediates increased endogenous fatty synthesis, and this Her-2/neu-mediated induction of breast cancer-associated FAS is inhibitable by trastuzumab. On the other hand, chemical FAS inhibitors as well as RNA interference-mediated silencing of FAS gene repress Her-2/neu gene expression at the transcriptional level. Moreover, specific FAS blockade synergistically sensitizes breast cancer cells carrying Her-2/neu-oncogene amplification and/or overexpression to trastuzumab-induced cell growth inhibition and apoptotic cell death. Strikingly, FAS inhibition synergistically interacts with trastuzumab in Her-2/neu-negative breast cancer cells engineered to overexpress Her-2/neu, thus suggesting that the molecular linkage between FAS activity and functioning of Her-2/neu cannot be explained only on the basis of a transcriptional repression of Her-2/neu gene promoter. Interestingly, while in liver and adipose tissue FAS produces fat from excess carbon consumed as carbohydrates, which is ultimately stored as triglycerides, in epithelial cancer cells, FAS activity is mainly involved in the production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), which point to an active role of FAS in the deregulation of membrane functioning in tumor cells. Importantly, clusters of Her-2/neu and EGFR (erbB-1) co-localize with lipid rafts and the lipid environment in the cell membrane of breast cancer cells profoundly influences their association properties and biological functions. We hypothesize that pharmacological or small interference RNA-induced inhibition of breast cancer-associated FAS will result in major changes in the synthesis of phospholipids which, in turn, should impair a correct cellular localization of Her-2/neu at the cellular membrane of breast cancer cells. In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas. PMID: 15780499 [PubMed - indexed for MEDLINE]