Pubs Related to Flaxseed AND Cancer

1: Clin Cancer Res. 2007 Feb 1;13(3):1061-7. Related Articles, Links

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Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of
vascular endothelial growth factor in human breast cancer xenografts in vivo.

Bergman Jungeström M, Thompson LU, Dabrosin C.

Divison of Oncology, Faculty of Health Sciences, University Hospital, Linköping, Sweden.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis,

which is crucial in cancer progression. We have previously shown that estradiol (E2) increases
VEGF in breast cancer. Phytoestrogens are potential compounds in breast cancer prevention and
treatment by poorly understood mechanisms. The main phytoestrogens in Western diet are
lignans, and flaxseed is a rich source of the mammalian lignans enterodiol and enterolactone.
EXPERIMENTAL DESIGN: In the present study, ovariectomized mice were treated with
continuous release of E2. MCF-7 tumors were established and mice were fed with basal diet or
10% flaxseed, and two groups that were fed basal diet received daily injections with enterodiol or
enterolactone (15 mg/kg body weight). RESULTS: We show that flaxseed, enterodiol, and
enterolactone counteracted E2-induced growth and angiogenesis in solid tumors. Extracellular
VEGF in vivo, sampled using microdialysis, in all intervention groups was significantly decreased
compared with tumors in the basal diet group. Our in vivo findings were confirmed in vitro. By
adding enterodiol or enterolactone, E2-induced VEGF secretion in MCF-7 cells decreased
significantly without agonistic effects. The increased VEGF secretion by E2 in MCF-7 cells
increased the expression of VEGF receptor-2 in umbilical vein endothelial cells, suggesting a
proangiogenic effect by E2 by two different mechanisms, both of which were inhibited by the
addition of lignans. CONCLUSIONS: Our results suggest that flaxseed and its lignans have
potent antiestrogenic effects on estrogen receptor-positive breast cancer and may prove to be
beneficial in breast cancer prevention strategies in the future.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 17289903 [PubMed - indexed for MEDLINE]

2: Clin Transl Oncol. 2006 Nov;8(11):812-20. Related Articles, Links

HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid
(ALA; 18:3n-3), in breast cancer cells: the "fat features" of the "Mediterranean diet" as an "anti-
HER2 cocktail".

Menéndez JA, Vázquez-Martín A, Ropero S, Colomer R, Lupu R.

Fundació d'Investigació Biomédica de Girona Dr. Josep Trueta (IdIBGi), Girona, Catalonia.
Spain. javiermenendez72@yahoo.com

BACKGROUND: Data derived from epidemiological and experimental studies suggest that
alphalinolenic acid (ALA; 18:3n-3), the main omega-3 polyunsaturated fatty acid (PUFA) present
in the Western diet, may have protective effects in breast cancer risk and metastatic progression.
A recent pilot clinical trial assessing the effects of ALA-rich dietary flaxseed on tumor biological
markers in postmenopausal patients with primary breast cancer demonstrated significant
reductions in tumor growth and in HER2 (erbB-2) oncogene expression. HYPOTHESIS: The
molecular mechanism by which ALA inhibits breast cancer cell growth and metastasis formation
may involve a direct regulation of HER2, a well-characterized oncogene playing a key role in the
etiology, progression and response to some chemo- and endocrine therapies in approximately
20% of breast carcinomas. METHODS: Using HER2-specific ELISA, flow cytometry,
immunofluorescence microscopy, Western blotting, RT-PCR and HER2 promoter-reporter
analyses, we characterized the effects of exogenous supplementation with ALA on the expression
of HER2 oncogene, a master key player in the onset and metastasis formation of breast cancer
disease. Metabolic status (MTT) assays were performed to evaluate the nature of the cytotoxic
interaction between ALA and the humanized anti-HER2 monoclonal antibody trastuzumab
(Herceptin). To study these issues we used BT-474 and SKBr-3 breast cancer cells, which
naturally exhibit amplification of the HER2 oncogene. RESULTS: ALA treatment dramatically
suppressed the expression of HER2-coded p185Her-2/neu oncoprotein as determined by ELISA,
flow cytometry, immunofluorescence microscopy and immunoblotting techniques. Interestingly,
ALA-induced down-regulation of p185Her-2/neu correlated with a transcriptional response as no
HER2 mRNA signal could be detected by RT-PCR upon treatment with optimal concentrations of
ALA (up to 20 microM). Consistent with these findings, ALA exposure was found to dramatically
repress the activity of a Luciferase reporter gene driven by the HER2 promoter. Moreover, the
nature of the cytotoxic interaction between ALA and trastuzumab (Herceptin) revealed a
significant synergism as assessed by MTT-based cell viability assays. CONCLUSIONS: i) These
findings reveal that the omega-3 PUFA ALA suppresses overexpression of HER2 oncogene at the
transcriptional level, which, in turn, interacts synergistically with anti-HER2 trastuzumab- based
immunotherapy. ii) Our results molecularly support a recent randomized double-blind placebo-
controlled clinical trial suggesting that ALA may be a potential dietary alternative or adjunct to
currently used drugs in the management of HER2-positive breast carcinomas. iii) Considering our
previous findings demonstrating the <<HER2 upregulatory actions>> of the omega-6 PUFA
linolenic acid (LA; 18:2n-6) and the <<HER2 down-regulatory actions >> of the omega-3 PUFA
docosahexaenoic acid (DHA; 22:6n-3) and of the omega-9 monounsaturated fatty acid oleic acid
(OA; 18:1n-9), it is reasonable to suggest that a low omega-6/omega-3 PUFA ratio and elevated
MUFA levels, the two prominent <<fat features>> of the <<Mediterranean diet>>, should be
extremely efficient at blocking HER2 expression in breast cancer cells.

Publication Types:

* Research Support, N.I.H., Extramural

* Research Support, Non-U.S. Gov't

PMID: 17134970 [PubMed - indexed for MEDLINE]

3: J Nutr. 2006 Apr;136(4):906-12. Related Articles, Links

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Sesamin is one of the major precursors of mammalian lignans in sesame seed (Sesamum
indicum) as observed in vitro and in rats.

Liu Z, Saarinen NM, Thompson LU.

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON,

M5S 3E2, Canada.

Plant lignans occur in many foods, with flaxseed presently recognized as the richest source.
Some plant lignans can be converted by intestinal microbiota to the mammalian lignans,
enterodiol and enterolactone, which may have protective effects against hormone-related
diseases such as breast cancer. This study determined whether plant lignans in sesame seed,
particularly sesamin, could be metabolized to the mammalian lignans. The total plant lignan
concentration in sesame seed (2180 micromol/100 g) was higher than that in flaxseed (820
micromol/100 g). In vitro fermentation with human fecal inoculum showed conversion of sesamin
to the mammalian lignans, although at a lower rate (1.1%) compared with that of
secoisolariciresinol diglucoside (57.2%). However, when fed to female Sprague-Dawley rats for
10 d, sesamin (15 mg/kg body weight) and a 10% sesame seed diet resulted in greater (P < 0.05)
urinary mammalian lignan excretion (3.2 and 11.2 micromol/d, respectively), than the control (<
0.05 micromol/d). We conclude that sesame seed is a rich source of mammalian lignan
precursors and sesamin is one of them. From intermediate metabolites of sesamin identified in rat
urine by GC-MS, a tentative metabolic pathway of sesamin to mammalian lignans is suggested.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 16549449 [PubMed - indexed for MEDLINE]

4: Int J Cancer. 2005 Sep 20;116(5):793-8. Related Articles, Links

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The inhibitory effect of flaxseed on the growth and metastasis of estrogen receptor negative
human breast cancer xenograftsis attributed to both its lignan and oil components.

Wang L, Chen J, Thompson LU.

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON,

Canada.

Our previous studies have shown that dietary flaxseed (FS) can reduce the growth and
metastasis of human estrogen receptor negative (ER-) breast cancer in nude mice. The aims of
our study were to determine (i) whether the tumor inhibitory effect of FS was due to its oil (FO),
lignan secoisolariciresinol diglycoside (SDG), or both components, and (ii) whether the effect on
tumor growth was related to increased lipid peroxidation. Athymic nude mice were orthotopically
injected with ER- breast cancer cells (MDA-MB-435) and 8 weeks later were fed either the basal
diet (BD) or BD supplemented with 10% FS, SDG, FO, or combined SDG and FO (SDG + FO) for
6 weeks. The SDG and FO levels were equivalent to the amounts in the 10% FS. Compared to
the BD group, the tumor growth rate was significantly lower (p < 0.05) in the FS, FO, and SDG +
FO groups, in concordance with decreased cell proliferation and increased apoptosis; however,
these did not significantly relate to the lipid peroxidation, indexed as malonaldehyde (MDA), in the
primary tumors. Lung metastasis incidence was reduced (16-70%) by all treatments, significantly
in the FS and SDG + FO groups. The distant lymph node metastasis was significantly decreased
(52%) only in the FO group. Although the total metastasis incidence was lowered (42%)
significantly only in the SDG + FO group, all treatment groups did not differ significantly. In
conclusion, FS reduced the growth and metastasis of established ER- human breast cancer in
part due to its lignan and FO components, and not to lipid peroxidation. (c) 2005 Wiley-Liss, Inc.

PMID: 15849746 [PubMed - indexed for MEDLINE]

5: Clin Cancer Res. 2005 May 15;11(10):3828-35. Related Articles, Links

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Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer.

Thompson LU, Chen JM, Li T, Strasser-Weippl K, Goss PE.

Department of Nutritional Sciences, Princess Margaret Hospital, University of Toronto, Toronto,

Ontario, Canada.

PURPOSE: Flaxseed, the richest source of mammalian lignan precursors, has previously been
shown to reduce the growth of tumors in rats. This study examined, in a randomized double-blind
placebo-controlled clinical trial, the effects of dietary flaxseed on tumor biological markers and
urinary lignan excretion in postmenopausal patients with newly diagnosed breast cancer.
EXPERIMENTAL DESIGN: Patients were randomized to daily intake of either a 25 g flaxseed-
containing muffin (n = 19) or a control (placebo) muffin (n = 13). At the time of diagnosis and
again at definitive surgery, tumor tissue was analyzed for the rate of tumor cell proliferation (Ki-67
labeling index, primary end point), apoptosis, c-erbB2 expression, and estrogen and
progesterone receptor levels. Twenty-four-hour urine samples were analyzed for lignans, and 3-
day diet records were evaluated for macronutrient and caloric intake. Mean treatment times were
39 and 32 days in the placebo and flaxseed groups, respectively. RESULTS: Reductions in Ki-67
labeling index (34.2%; P = 0.001) and in c-erbB2 expression (71.0%; P = 0.003) and an increase
in apoptosis (30.7%; P = 0.007) were observed in the flaxseed, but not in the placebo group. No
significant differences in caloric and macronutrient intake were seen between groups and
between pre- and posttreatment periods. A significant increase in mean urinary lignan excretion
was observed in the flaxseed group (1,300%; P < 0.01) compared with placebo controls. The total
intake of flaxseed was correlated with changes in c-erbB2 score (r = -0.373; P = 0.036) and
apoptotic index (r = 0.495; P < 0.004). CONCLUSION: Dietary flaxseed has the potential to
reduce tumor growth in patients with breast cancer.

Publication Types:

* Clinical Trial
* Randomized Controlled Trial
* Research Support, Non-U.S. Gov't

PMID: 15897583 [PubMed - indexed for MEDLINE]

6: Anticancer Res. 2005 May-Jun;25(3A):1817-22. Related Articles, Links

Flax-seed extracts with phytoestrogenic effects on a hormone receptor-positive tumour cell

line.

Waldschläger J, Bergemann C, Ruth W, Effmert U, Jeschke U, Richter DU, Kragl U, Piechulla

B, Briese V.

Department of Obstetrics and Gynaecology, University of Rostock, Germany.

juliane.waldschlaeger@kliniksued-rostock.de

The higher soy intake in the Asian population compared to Europeans is believed to be an
essential factor for the lower incidence of hormone-dependent tumours in Asia. It has already
been shown that soya beans, with their ingredients genistein and daidzein from the isoflavonoid
group, have protective effects on hormone-caused diseases. Lignans are another, less
investigated, group of phytoestrogens. The aim of this study was to investigate the effects of flax-
seed, which is typically found in Northern European diets, on the proliferation and hormone
production of an estrogen receptor (ER)-positive trophoblast tumour cell line. MATERIALS AND
METHODS: Trophoblast tumour cells of the cell line Jeg3 were incubated with 2 different
concentrations of the isolated crude extract of flax-seed and 7 chemically partitioned extract
fractions. Untreated cells were used as controls. After 48 h of stimulation, cell proliferation was
measured using the BrdU method. The concentrations of hCG and progesterone produced by the
trophoblast tumour cells were measured 48 h after stimulation. Extract fractions with
antiproliferative effects in the BrdU- test were analysed by HPLC-MS. RESULTS: Our study
showed an inhibitory influence of some of the isolated flax-seed fractions on the Jeg3 tumour
cells. Proliferation of the Jeg3 cells was decreased by flax-seed fractions I, V, VI and VII in a
dose-dependent manner. Inhibition of hCG production by flax-seed extracts III, V, VI and VII was
also dose-dependent. Extract fractions V and VI decreased the production of progesterone by
58% to 86%. Some extract fractions showed a stimulating effect on hormone production and cell
proliferation. HPLC-MS analysis showed the presence of matairesinol and biochanin A in flax-
seed fraction VI. DISCUSSION: Flax-seed seems to have similar inhibitory effects to soya on
hormone production and proliferation of hormone-sensitive tumour cells. Our results showed a
dose-dependent inhibition by isolated flax-seed extracts on the Jeg3 cell line. Matairesinol and
biochanin A seem to be useful candidates for extended tests on other tumour cell lines and
normal tissues to evaluate the potential benefit of a lignan-containing therapy in hormone-
dependent diseases.

PMID: 16033105 [PubMed - indexed for MEDLINE]

7: Forum Nutr. 2005;(57):100-11. Related Articles, Links

Health effects of phytoestrogens.

Branca F, Lorenzetti S.

National Institute for Research on Food and Nutrition, Rome, Italy. f.branca@agora.it

Phytoestrogens are naturally occurring plant-derived phytochemicals, whose common

biological roles are to protect plants from stress or to act as part of a plant's defense mechanism.
Although composed of a wide group of nonsteroidal compounds of diverse structure,
phytoestrogens have been shown to bind estrogen receptors and to behave as weak
agonist/antagonist in both animals and humans. Phytoestrogens include mainly isoflavones (IF),
coumestans, and lignans. These compounds are known to be present in fruits, vegetables, and
whole grains commonly consumed by humans. IF are found in legumes--mainly soybeans--
whereas flaxseed is a major source of lignans, and coumestans are significantly present in clover,
alfalfa and soybean sprouts. 8-Prenyl flavonoids are common in vegetables. Bioavailability of IF
requires an initial hydrolysis of the sugar moiety by intestinal beta-glucosidases to allow the
following uptake by enterocytes and the flow through the peripheral circulation. Following
absorption, IF are then reconjugated mainly to glucuronic acid and to a lesser degree to sulphuric
acid. Gut metabolism seems key to the determination of the potency of action. Several
epidemiological studies correlated high dose consumptions of soy IF with multiple beneficial
effects on breast and prostate cancers, menopausal symptoms, osteoporosis, atherosclerosis
and stroke, and neurodegeneration. For the relief of menopausal symptoms a consumption of 60
mg aglycones/day has been suggested; for cancer prevention a consumption between 50 and
110 mg aglycones/day is considered beneficial to reduce risks of breast, colon and prostate
cancer; to decrease cardiovascular risk a minimum intake of 40-60 mg aglycones/day, together
with about 25 g of soy protein has been suggested. For improvement in bone mineral density, 60-
100 mg aglycones/day for a period of at least 6-12 months could be beneficial.

Publication Types:

* Review

PMID: 15702593 [PubMed - indexed for MEDLINE]