More suggestions as to potential links between omega six and breast cancer.
It is interesting that Tamoxifen seems to be active in the fats pathways.
Is denying the body excess Arachnidonic Acid in the first place by restricting iintake to a level that is balance with the omega threes an alternative and adjunctive control mechanism as well as a possible preventative.
I know its complicated.
But for me the gist stands out - omega six may have a part to play in the disease of BC.
It would cost rather less and be very much easier to determine if it does than looking for ways to arbitrate an excess of intake - and that is without considering the consequences to national health budgets, the social consequencies of health rationing by ability to pay if drugs become unaffordable, human wellfare etc.
RB
http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum
1: J Pharm Pharmacol. 1987 Apr;39(4):323-4. Related Articles, Links
Tamoxifen inhibits 5-lipoxygenase in human polymorphonuclear leucocytes.
Tavares IA, Stamford IF, Bennett A.
Breast cancer patient survival is increased by tamoxifen, and we therefore need to understand how this drug exerts its effect. We describe a novel action of tamoxifen, the inhibition of LTB4 and 5-HETE production from [14C]-arachidonic acid by human polymorphonuclear leucocytes.
PMID: 2884303 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum
1: Biochem Biophys Res Commun. 2002 Aug 30;296(4):942-8. Related Articles, Links
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The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells.
Tong WG, Ding XZ, Adrian TE.
Department of Surgery, Gastrointestinal Oncology Laboratories, Northwestern University Medical School, Chicago, IL 60611, USA.
Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.
PMID: 12200139 [PubMed - indexed for MEDLINE]
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1: FASEB J. 2001 Sep;15(11):2007-9. Epub 2001 Jul 9. Related Articles, Links
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Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions.
Avis I, Hong SH, Martinez A, Moody T, Choi YH, Trepel J, Das R, Jett M, Mulshine JL.
Intervention Section, Department of Cell and Cancer Biology, Division of Clinical Sciences, National Cancer Institute, NIH Clinical Center, 9000 Rockville Pike, Bethesda, MD 20892-1906, USA.
Many arachidonic acid metabolites function in growth signaling for epithelial cells, and we previously reported the expression of the major arachidonic acid enzymes in human breast cancer cell lines. To evaluate the role of the 5-lipoxygenase (5-LO) pathway on breast cancer growth regulation, we exposed cells to insulinlike growth factor-1 or transferrin, which increased the levels of the 5-LO metabolite, 5(S)-hydrooxyeicosa-6E,8C,11Z,14Z-tetraenoic acid (5-HETE), by radioimmunoassay and high-performance liquid chromatography. Addition of 5-HETE to breast cancer cells resulted in growth stimulation, whereas selective biochemical inhibitors of 5-LO reduced the levels of 5-HETE and related metabolites. Application of 5-LO or 5-LO activating protein-directed inhibitors, but not a cyclooxygenase inhibitor, reduced growth, increased apoptosis, down-regulated bcl-2, up-regulated bax, and increased G1 arrest. Exposure of breast cancer cells to a 5-LO inhibitor up-regulated peroxisome proliferator-activated receptor (PPAR)a and PPARg expression, and these same cells were growth inhibited when exposed to relevant PPAR agonists. These results suggest that disruption of the 5-LO signaling pathway mediates growth arrest and apoptosis in breast cancer cells. Additional experiments suggest that this involves the interplay of several factors, including the loss of growth stimulation by 5-LO products, the induction of PPARg, and the potential activation of PPARg by interactions with shunted endoperoxides.
PMID: 11511519 [PubMed - indexed for MEDLINE]
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1: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13182-7. Related Articles, Links
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Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.
Ghosh J, Myers CE.
University of Virginia Cancer Center, Charlottesville, VA 22908, USA.
Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer.
PMID: 9789062 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum
1: Clin Exp Metastasis. 1996 Mar;14(2):145-52. Related Articles, Links
Eicosanoids as mediators of linoleic acid-stimulated invasion and type IV collagenase production by a metastatic human breast cancer cell line.
Liu XH, Connolly JM, Rose DP.
Division of Nutrition and Endocrinology, American Health Foundation, Valhalla, New York 10595, USA.
Diets rich in linoleic acid (LA) stimulate the metastasis of MDA-MB-435 human breast cancer cells from the mammary fat pads of nude mice. This omega-6 fatty acid is metabolized to various cyclo-oxygenase and lipoxygenase products, several of which have been previously associated with tumor cell invasion and metastasis. We now report that MDA-MB-435 cells secreted increased levels of prostaglandin E2 (PGE2), and 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE when cultured in the presence of 2.7 microM (0.75 micrograms/ml) LA; 5-HETE secretion was unchanged. The 12-lipoxygenase inhibitor esculetin (20 microM) completely blocked the LA-stimulated 12-HETE secretion. Linoleic acid also increased MDA-MB-435 cell invasion in an in vitro assay; this stimulation was abolished by 20 microM esculetin, but was unaffected by piroxicam, a selective cyclooxygenase inhibitor. The effect of LA on invasion was replicated by 0.1 microM 12-HETE, but not by 5-HETE or PGE2; 15-HETE was stimulatory only at a concentration of 1.0 microM. Zymographic and Northern blot analyses showed that these events are accompanied by the induction of 92 kDa isoform type IV collagenase (metalloproteinase-9) enzymic activity and mRNA expression by exogenous LA and 12-HETE, and their suppression by the 12-lipoxygenase inhibitor. These results suggest that the effects of dietary LA on breast cancer cell metastasis in the nude mouse model are due, at least in part, to enhanced 12-HETE biosynthesis, with an associated increase in proteolytic enzyme activity and tumor cell invasiveness.
PMID: 8605728 [PubMed - indexed for MEDLINE]
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