Cecal microbiota and mammary gland microRNA signatures are related and modifiable by dietary flaxseed with implications for breast cancer risk.

Breast cancer is a leading cause of cancer mortality worldwide. There is a growing interest in using dietary approaches, including flaxseed (FS) and its oil and lignan components, to mitigate breast cancer risk. Importantly, there is recognition that pubertal processes and lifestyle, including diet, are important for breast health throughout life.

MicroRNAs: A Link between Mammary Gland Development and Breast Cancer.

Breast cancer is among the most common cancers in women, second to skin cancer. Mammary gland development can influence breast cancer development in later life. Processes such as proliferation, invasion, and migration during mammary gland development can often mirror processes found in breast cancer.

Data on mammary gland microRNAs expression, their predicted gene targets and corresponding pathway analysis in female mice receiving flaxseed or its oil and secoisolariciresinol diglucoside components.

Dietary flaxseed may act via microRNAs (miRNAs) to affect the health of the mammary gland. These data are in support of the article entitled "Effects of flaxseed and its components on mammary gland miRNome: identification of potential biomarkers to prevent breast cancer development" [1]. Here, we provide miRNA expression data obtained from NanoString nCounter® profiling of mammary gland RNA from C57BL/6 female mice who received a control diet or isocaloric diets containing 10% FS, 3.

Data on cecal and fecal microbiota and predicted metagenomes profiles of female mice receiving whole flaxseed or its oil and secoisolariciresinol diglucoside components.

Dietary flaxseed (FS) and its components including FS oil (FSO), secoisolariciresinol diglucoside (SDG) and fiber, are processed by the gut microbiota. These data are in support of the article entitled "Discriminatory and cooperative effects within the mouse gut microbiota in response to flaxseed and its oil and lignan components", Journal of Nutritional Biochemistry [1]. Here we describe data generated by 16S rRNA sequencing of DNA obtained from cecum contents and feces of C57BL/6 female mice fed either a basal diet (BD, AIN93G), or isocaloric diets containing 10% FS, or 10% FS-equivalent amounts of FSO or SDG for 21 days.

Discriminatory and cooperative effects within the mouse gut microbiota in response to flaxseed and its oil and lignan components.

Gut microbial processing of dietary flaxseed (FS) contributes to its health benefits, but the relative effects of its bioactive components (lignans, omega-3 fatty acids, fiber) on the microbiota are unclear. We investigated the gut microbial compositional and functional responses to whole FS and its isolated components, FS oil (FSO) and secoisolariciresinol diglucoside (SDG) (precursor to microbial-derived enterolignans) to help understand their contribution to whole FS benefits. Cecum content and fecal samples were collected from C57BL/6 female mice fed a basal diet (AIN93G) or isocaloric diets containing 10% FS or 10% FS-equivalent amounts of FSO or SDG for 21 days.

Enterolignan Production in a Flaxseed Intervention Study in Postmenopausal US Women of African Ancestry and European Ancestry.

Lignans are phytochemicals studied extensively as dietary factors in chronic disease etiology. Our goal was to examine associations between the gut microbiota and lignan metabolism and whether these associations differ by ethnicity. We conducted a flaxseed (FS) dietary intervention in 252 healthy, postmenopausal women of African ancestry (AA) and European ancestry (EA).

Effects of Flaxseed and Its Components on Mammary Gland MiRNome: Identification of Potential Biomarkers to Prevent Breast Cancer Development.

Breast cancer is the most common cancer among women worldwide. We previously showed that early-life exposure to flaxseed (FS) or its components, FS oil (FSO) and secoisolariciresinol diglucoside (SDG), affects the mammary gland (MG) and is associated with the reduction of breast cancer risk during adulthood. However, the underlying mechanisms are not understood.

Genetic Variation in Steroid and Xenobiotic Metabolizing Pathways and Enterolactone Excretion Before and After Flaxseed Intervention in African American and European American Women.

Background: Metabolism and excretion of the phytoestrogen enterolactone (ENL), which has been associated with breast cancer risk, may be affected by variation in steroid hormone and xenobiotic-metabolizing genes.

Methods: We conducted a randomized, crossover flaxseed intervention study in 252 healthy, postmenopausal women [137 European ancestry (EA) and 115 African ancestry (AA)] from western New York. Participants were randomly assigned to maintain usual diet or consume 10 g/day ground flaxseed for 6 weeks.

Effect of Dietary Flaxseed Intake on Circulating Sex Hormone Levels among Postmenopausal Women: A Randomized Controlled Intervention Trial.

Lignan intake, and its richest food source, flaxseed, have been associated with reduced breast cancer risk. Endogenous sex hormones, such as estrogens, play a role in breast cancer development, and lignans may alter these sex hormone levels. To assess the effect of flaxseed on circulating sex hormones, a randomized controlled trial was conducted among 99 postmenopausal women in Toronto, Canada.

Omega-3 Polyunsaturated Fatty Acids Time-Dependently Reduce Cell Viability and Oncogenic MicroRNA-21 Expression in Estrogen Receptor-Positive Breast Cancer Cells (MCF-7).

The omega-3 polyunsaturated fatty acid (n-3 PUFA), α-linolenic acid (ALA), and its metabolites, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), independently reduce the growth of breast cancer cells in vitro, but the mechanisms, which may involve microRNA (miRNA), are still unclear. The expression of the oncomiR, miR-21, is reduced by DHA treatment, but the effects of ALA on miR-21, alone or combined with EPA and DHA under physiologically relevant concentrations, have not been investigated. The effects of ALA alone and +/-EPA and DHA at the blood molar ratios seen in either humans (1.

α-linolenic acid and docosahexaenoic acid, alone and combined with trastuzumab, reduce HER2-overexpressing breast cancer cell growth but differentially regulate HER2 signaling pathways.

Background: Diets rich in the n-3 fatty acid alpha-linolenic acid (ALA) have been shown to reduce breast tumor growth, enhance the effectiveness of the HER2-targeted drug trastuzumab (TRAS) and reduce HER2 signaling in mouse models. It is unclear whether this is due to direct effects of ALA or due to its long-chain n-3 fatty acids metabolites including docosahexaenoic acid (DHA).

Methods: The ability of HER2-overexpressing BT-474 human breast cancer cells to convert ALA to long-chain n-3 fatty acids was determined by measurement of phospholipid fatty acids by gas chromatography following treatment with 100 μM ALA.

α-Linolenic Acid Reduces Growth of Both Triple Negative and Luminal Breast Cancer Cells in High and Low Estrogen Environments.

Flaxseed, rich in α-linolenic acid (ALA), is a complementary breast cancer (BC) therapy; however ALA effectiveness and mechanism are unclear. Variation in cellular expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and estrogen (E2) levels may alter ALA effectiveness. This research determined the effect of ALA on growth, apoptosis, and phospholipid fatty acids of 4 BC cell lines with varying receptor expression ± E2.

Growth and gene expression differ over time in alpha-linolenic acid treated breast cancer cells.

Scope: Heterogeneity of breast cancer (BC) subtypes makes BC treatment difficult. α-linolenic acid (ALA), rich in flaxseed oil, has been shown to reduce growth and increase apoptosis in several BC cell lines, but the mechanism of action needs further understanding.

Methods And Results: Four BC cell lines (MCF-7, BT-474, MDA-MB-231 and MDA-MB-468) were incubated with 75 μM ALA+1 nM 17-β estradiol (E2) or 1 nM E2 only (control) for 24 h.

Flaxseed oil enhances the effectiveness of trastuzumab in reducing the growth of HER2-overexpressing human breast tumors (BT-474).

Flaxseed oil (FSO) reduces breast tumorigenesis and HER2 expression in animal models of luminal breast cancer. The primary treatment for HER2-overexpressing tumors is trastuzumab (TRAS). We aimed to determine the effect of 4% FSO alone and combined with TRAS on HER2-overexpressing tumor (BT-474) growth and to explore potential mechanisms with a specific focus on HER2, mitogen-activated protein kinase (MAPK) and Akt signaling and fatty acid profile.

17β-estradiol increases liver and serum docosahexaenoic acid in mice fed varying levels of α-linolenic acid.

Docosahexaenoic acid (DHA) is considered to be important for cardiac and brain function, and 17β-estradiol (E2) appears to increase the conversion of α-linolenic acid (ALA) into DHA. However, the effect of varying ALA intake on the positive effect of E2 on DHA synthesis is not known. Therefore, the objective of this study was to investigate the effects of E2 supplementation on tissue and serum fatty acids in mice fed a low-ALA corn oil-based diet (CO, providing 0.

Flaxseed and its lignan and oil components: can they play a role in reducing the risk of and improving the treatment of breast cancer?

Flaxseed (FS), rich in the phytoestrogen lignans and α-linolenic acid-rich oil, has been suggested to have an anticancer effect. Questions remain whether FS and its lignan and oil components are effective in reducing breast cancer risk and tumour growth, and can interact beneficially with breast cancer drugs. To find answers, in vitro, animal, observational, and clinical studies on FS and its lignan and oil components were reviewed.

Flaxseed enhances the beneficial effect of low-dose estrogen therapy at reducing bone turnover and preserving bone microarchitecture in ovariectomized rats.

Our previous research showed greatest protection to vertebral bone mineral density and strength in ovariectomized (OVX) rats when lignan- and α-linolenic acid-rich flaxseed (FS) is combined with low-dose estrogen therapy (LD) compared with either treatment alone. This study determined the effects of combined FS+LD on serum and tissue markers of bone turnover and microarchitecture to explain our previous findings. Three-month-old OVX rats were randomized to negative control (NEG), FS, LD or FS+LD for 2 or 12 weeks, meaningful time points for determining effects on markers of bone metabolism and bone structure, respectively.

A pilot study comparing the effect of flaxseed, aromatase inhibitor, and the combination on breast tumor biomarkers.

Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS), are not often described. We conducted a pilot 2 × 2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER+) breast cancer, to assess the effects of FS and anastrozole, and possible interactions between them, on serum steroid hormone and tumor-related characteristics associated with long-term survival (Roswell Park Cancer Institute, 2007-2010).

Dietary flaxseed-trastuzumab interactive effects on the growth of HER2-overexpressing human breast tumors (BT-474).

Flaxseed (FS) reduces breast tumorigenesis and human epidermal growth factor receptor 2 (HER2) expression in postmenopausal patients and animal models. The primary treatment for HER2-overexpressing tumors is trastuzumab (TRAS). FS oil enhances TRAS effectiveness in athymic mice but the FS effect is unknown and was therefore determined.

Use of isoflavone supplements is associated with reduced postmenopausal breast cancer risk.

Botanical supplements are widely used and contain diverse ingredients, including isoflavones. Food-based isoflavones have been associated with reduced breast cancer risk. However, no study has comprehensively evaluated supplements identified by isoflavone content and breast cancer risk.

Flaxseed does not enhance the estrogenic effect of low-dose estrogen therapy on markers of uterine health in ovariectomized rats.

Flaxseed (FS) is an oilseed rich in phytoestrogens and n-3 polyunsaturated fatty acids, compounds that may attenuate bone loss during aging. We previously demonstrated using the ovariectomized (OVX) rat model of postmenopausal osteoporosis that 10% dietary FS combined with low-dose estrogen therapy (LD) preserves vertebral bone mass and strength more so than either treatment alone. However, it was prudent to also consider the effect of this intervention on uterine tissue as LD, and possibly FS, may have estrogenic, and thus negative, effects on uterine tissue.

Comparative effects of sesame seed lignan and flaxseed lignan in reducing the growth of human breast tumors (MCF-7) at high levels of circulating estrogen in athymic mice.

Flaxseed (FS) has a breast tumor-reducing effect, possibly because of its high content of secoisolariciresinol diglucoside (SDG) lignan. Sesame seed (SS) is rich in the lignan sesamin (SES) but is non-protective. Both lignans are metabolized to estrogen-like enterodiol and enterolactone.

Dietary intakes of total and specific lignans are associated with clinical breast tumor characteristics.

Dietary lignans may affect breast cancer by modifying tumor characteristics likely to affect prognosis. We investigated usual dietary intakes of total and specific lignans with tumor characteristics in 683 women with breast cancer and 611 healthy women without breast cancer enrolled in the Data Bank and BioRepository at Roswell Park Cancer Institute (RPCI). Clinicopathologic data were abstracted from the RPCI breast cancer database.

Accessibility of ³H-secoisolariciresinol diglycoside lignan metabolites in skeletal tissue of ovariectomized rats.

Flaxseed, rich in the phytoestrogen lignan secoisolariciresinol diglycoside (SDG), provides protection against bone loss at the lumbar vertebrae primarily when combined with low-dose estrogen therapy in the ovariectomized rat model of postmenopausal osteoporosis. Whether SDG metabolites are accessible to skeletal tissue, and thus have the potential to interact with low-dose estrogen therapy to exert direct local action on bone metabolism, is unknown. The objective of this study was to determine whether metabolites of SDG are accessible to the skeleton of ovariectomized rats and to compare the distribution of SDG metabolites in skeletal tissue with that in other tissues.

Effects of flaxseed lignan and oil on bone health of breast-tumor-bearing mice treated with or without tamoxifen.

Previous studies showed that flaxseed lignan (secoisolariciresinol diglucoside, SDG) and oil (FO) inhibit established breast tumor growth in athymic mice with or without tamoxifen (TAM) treatment. TAM was found to increase bone mineral content (BMC) and density (BMD) in breast cancer patients. It is not known whether SDG or FO alone or combined with TAM affects bone health.