Flaxseed Alone or in Combination with Tamoxifen Inhibits MCF-7 Breast Tumor Growth in Ovariectomized Athymic Mice with High Circulating Levels of Estrogen

Chen, Jianmin; Power, Krista A.; Mann, Jaskaren; Cheng, Arthur H.; Thompson, Lilian U.

doi:10.3181/0702-rm-36

Cited by 56 publications

(58 citation statements)

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“…The basal diet (BD) control was prepared based on the AIN-93G diet [17], modified to contain 20% fat from corn oil instead of soybean oil due to its low levels of phytosterols and n-3 fatty acids to minimize confounding factors. The anti-cancer effects of FS have been tested in both high [9] and low [10][11] fat diets and the results are similar. However, the high-fat diet established the tumors faster and therefore was used in the present study.…”

Section: Animals and Dietsmentioning

confidence: 52%

“…Previous studies in carcinogen-treated rats and in athymic mice with xenografts of ER1 or estrogen receptor negative (ERÀ) human breast tumors have shown that dietary FS can reduce the growth of established tumors [9][10][11][12][13]. Similarly, in a study of postmenopausal breast cancer patients, FS has been shown to reduce tumor-cell proliferation and HER2 protein expression and increase apoptosis [14].…”

Section: Introductionmentioning

confidence: 98%

“…Similarly, in a study of postmenopausal breast cancer patients, FS has been shown to reduce tumor-cell proliferation and HER2 protein expression and increase apoptosis [14]. In the ovariectomized (OVX) athymic mouse model, dietary 5 or 10% FS also did not interfere with but rather enhanced the tumor growth inhibitory effect of TAM at high circulating estrogen levels [9][10] and attenuated the tumor stimulatory/estrogenic effects of long-term exposure to TAM at low circulating estrogen levels [11]. However, it is unknown whether the beneficial effects of FS may be attributed to its SDG lignan, ALA-rich oil components or their combination, and the mechanisms whereby they act in combination with TAM are unclear.…”

Section: Introductionmentioning

confidence: 99%

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Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF‐7 tumor growth through estrogen receptor‐ and growth factor‐signaling pathways

Saggar

Chen

Corey

et al. 2010

Molecular Nutrition Food Res

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This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels, and potential mechanisms of action. In a 2 x 2 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER-mediated (ER-alpha, ER-beta, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor-mediated (epidermal growth factor receptor, human epidermal growth factor receptor-2, insulin-like growth factor receptor-1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM-treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM-treated tumors but FO was more effective. The mechanisms involve both the ER- and growth factor-signaling pathways.

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Section: Animals and Dietsmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF‐7 tumor growth through estrogen receptor‐ and growth factor‐signaling pathways

Saggar

Chen

Corey

et al. 2010

Molecular Nutrition Food Res

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“…Lignan-rich flaxseed has been reported to attenuate E2-stimulated growth of human MCF-7 breast cancer xenografts in athymic mice, 40 and similar attenuation of E2-enhanced MCF-7 tumor growth was recently demonstrated with the enterolignans enterodiol and enterolactone. 27 Here, we demonstrated that intake of lariciresinol, a precursor of secoisolariciresinol and enterolignans, was able to delay E2-stimulated growth of the MCF-7 tumors, in line with previous reports.…”

Section: Discussionmentioning

confidence: 99%

Dietary lariciresinol attenuates mammary tumor growth and reduces blood vessel density in human MCF‐7 breast cancer xenografts and carcinogen‐induced mammary tumors in rats

Saarinen

Wärri

Dings

et al. 2008

Intl Journal of Cancer

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Lariciresinol is a dietary lignan that accounts for a significant portion of the total phytoestrogen intake from Western foods. Recent epidemiological studies suggest that high dietary intake of lignans and lariciresinol is associated with reduced breast cancer risk. However, no causal relationship between lariciresinol intake and breast cancer development has been established. In this study, we investigated for the first time the effects and possible mechanisms of action of lariciresinol on hormone responsive mammary cancer in vivo in dimethylbenz [a]anthracene induced mammary cancer in rats, and in human MCF-7 breast cancer xenografts in athymic mice. For tumor bearing rats, lariciresinol (3 or 15 mg/kg of body weight) or vehicle was administered p.o. daily for 9 weeks. For E2-maintained ovariectomized athymic mice bearing orthotopic MCF-7 tumors, control diet (AIN-93G) or lariciresinol containing diet (AIN-93G supplemented with 20 or 100 mg of lariciresinol/kg of diet) was administered for 5 weeks. In both models, lariciresinol administration inhibited the tumor growth and tumor angiogenesis. In MCF-7 cells, enterolactone significantly inhibited the E2-stimulated VEGF secretion. Moreover, in MCF-7 xenografts, lariciresinol administration enhanced tumor cell apoptosis and increased estrogen receptor beta expression. Lariciresinol and its further metabolites secoisolariciresinol, enterodiol and enterolactone were found in serum of both rats and athymic mice confirming a similar lignan metabolism pattern as in humans. These findings indicate conceivable importance of dietary lignan lariciresinol in inhibition of breast cancer development.

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“…Tumors were digitally measured (ScionImage; Scion Corp., Frederick, MD, USA) and tumor cross-sectional areas calculated by the formula (length ⁄ 2 · width ⁄ 2) · p as previously described. (23) Histopathological and immunohistochemical analyses. Tumors were dissected into approximately 50 volumes of 10% buffered formalin and fixed for 3 days prior to paraffin embedding.…”

Section: Methodsmentioning

confidence: 99%

Enhanced tumor growth in the NaS1 sulfate transporter null mouse

et al. 2010

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Sulfate plays an important role in maintaining normal structure and function of tissues, and its content is decreased in certain cancers including lung carcinoma. In this study, we investigated tumor growth in a mouse model of hyposulfatemia (Nas1 ) ⁄ ) ) and compared it to wild-type (Nas1 + ⁄ + ) mice. Lung epithelial tumor cells (TC-1 cell line) were injected subcutaneously into male Nas1and Nas1 + ⁄ + mice on a mixed 129Sv and C57BL ⁄ 6 genetic background. Tumor sections were stained with anti-glycosaminoglycan antibodies to assess the distribution of proteoglycans and Gomori's trichrome to detect collagen. After 14 days, tumor weights were markedly increased (by 12-fold) in Nas1) ⁄ ) mice when compared with Nas1 + ⁄ + mice. Histological analyses of tumors revealed increased (by 2.4-fold) vessel content, as well as markedly reduced collagen and immunoreactivity against glycosaminoglycan structural epitopes in the tumors from Nas1 ) ⁄ ) mice. No significant differences were found for the growth of cultured TC-1 cells supplemented with Nas1) ⁄ ) or Nas1 + ⁄ + serum, as determined by 3 H-thymidine incorporation, implying that the cell culture conditions may not reflect the in vivo situation of enhanced tumor growth. This study has revealed increased tumor growth and an altered extracellular tumor matrix in hyposulfatemic Nas1) ⁄ ) mice. These findings highlight the importance of blood sulfate levels as a possible modulator of tumor growth, and could lead to future cancer studies in humans with altered sulfate homeostasis. (Cancer Sci 2010; 101: 369-373) S ulfate (SO 4 2) ) is an abundant anion in the human body and is essential for numerous cellular and metabolic processes.(1) SO 4 2) conjugation or sulfonation of glycosaminoglycans (GAGs) is important for maintaining the structure and function of tissues.(2) Heparan sulfate proteoglycans (HSPGs) are a group of variably sulfonated GAGs found at the cell surface and extracellular matrix, which play a major role in regulating growth factor signaling in tumors.(3) In particular, the sulfate content of HSPGs is a critical factor in modulating tumor growth and angiogenesis.(4) Desulfonation of HSPGs by sulfatases promotes the release of growth factors that enhance tumor growth, (5) and increased sulfatase activity is associated with a poor prognosis in patients with hepatocellular carcinoma, breast, and pancreatic cancers. (6)(7)(8) In addition, the removal of highly sulfonated regions of HSPGs, using heparanase I, leads to accelerated tumor growth, neovascularization, and decreased apoptosis in a mouse model of lung carcinoma.(3) Highly sulfonated HSPGs or heparins, as well as sulfonated polymers such as laminarin sulfate, act as inhibitors of heparanase activity and have beneficial outcomes in preventing tumor growth and angiogenesis in vivo.(9) These studies highlight the importance of sulfate in modulating tumor growth and angiogenesis. SO 4 2) is obtained directly from the diet and from the oxidation of sulfur containing amino acids, methionine and cysteine....

show abstract

Flaxseed Alone or in Combination with Tamoxifen Inhibits MCF-7 Breast Tumor Growth in Ovariectomized Athymic Mice with High Circulating Levels of Estrogen

Cited by 56 publications

References 47 publications

Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF‐7 tumor growth through estrogen receptor‐ and growth factor‐signaling pathways

Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF‐7 tumor growth through estrogen receptor‐ and growth factor‐signaling pathways

Dietary lariciresinol attenuates mammary tumor growth and reduces blood vessel density in human MCF‐7 breast cancer xenografts and carcinogen‐induced mammary tumors in rats

Enhanced tumor growth in the NaS1 sulfate transporter null mouse

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