The present study was designed to investigate the influence of the dietary phytoestrogens enterolactone and genistein on breast cancer angiogenic factors. Formation of new blood vessels is an important element of cancer progression and its regulators are released both by the cancer cells and the stroma. Stroma, which is interposed between cancer cells and normal host tissues, is essential for tumor growth. Dietary phytoestrogens, such as the lignan enterolactone and the isoflavone genistein, may influence breast cancer growth differently. In the study, human hormone receptor positive (ER+/PR+) MCF-7 breast cancer cells were transplanted into ovariectomized athymic mice, creating a tumor. The mice were fed one of four diets supplemented with estradiol (E2): (1) control basal AIN-93G diet (basal diet); (2) basal diet supplemented with 100 mg/kg enterolactone; (3) basal diet supplemented with 100 mg/kg genistein; or (4) basal diet supplemented with their combination (enterolactone+genistein). Both the enterolactone and enterolactone+genistein diets were found to inhibit E2-induced cancer growth and angiogenesis while genistein alone did not. Extracellular proteins in mice tumors were sampled using microdialysis. Both enterolactone and enterolactone+genistein were observed to result in a reduction of both stroma- and cancer cell-derived vascular endothelial growth factor (VEGF), whereas cancer cell-derived placenta growth factor (PlGF) was found to increase. Furthermore, enterolactone and enterolactone+genistein reduced E2-induced endothelial cell infiltration while genistein alone did not. Finally, in endothelial cells, E2-induced VEGFR-2 expression was inhibited by enterolactone but not by genistein. The authors conclude that dietary enterolactone has powerful anti-estrogenic effects on breast cancer growth (even in combination with genistein) by down regulating E2-stimulated angiogenic factors derived both from the stroma and the cancer cells while genistein does not posses any anti-estrogenic effects.

The present study examined the production of enterolactone, a lignan phytoestrogen, in rats fed a diet supplemented with wheat bran. The dietary origin of lignan phytoestrogens is still not well understood more than 20 years after their discovery in human urine. However, urinary lignan phytoestrogen level have been found to be related to the consumption of dietary fiber. In the study, rats were fed a diet supplemented with 15% wheat bran for two weeks. Enterolactone excretion was found to increase continuously during the study to reach a value of 45 nmol per day. The level of excretion also increased upon preadaptation to ferulic acid (which is structurally related to secoisolariciresinol, an established precursor of enterolactone in flaxseeds), and declined upon preadaptation to fiber-rich potato starch. The authors comment that the results show that the formation of lignans from wheat bran is influenced by the diet, possibly because of an adaptation of the colonic microflora.

The present analysis examines the relationship between plant lignan intake and breast cancer. Lignans are the main class of phytoestrogens in the Western diet. Phytoestrogens, which are plant compounds structurally similar to estradiol, have been proposed to protect against breast cancer. However, studies on the effect of lignans in breast cancer risk have yielded conflicting results. The authors performed three separate meta-analyses to examine the relationships between (1) plant lignan intake, (2) enterolignan exposure, and (3) blood enterolactone levels and risk of breast cancer. Twenty-three studies were included in the random effects meta-analyses. Overall, little association was found between high plant lignan intake and overall breast cancer risk (11 studies, combined odds ratio (OR) = 0.93, 95% confidence interval (95% CI): 0.83 - 1.03, P=0.15). However, when the analysis was restricted to postmenopausal women, high levels of plant lignan intake were found to be associated with reduced breast cancer risk (7 studies, combined OR = 0.85, 95% CI: 0.78 - 0.93, P<0.001) and the results were fairly consistent across the studies. High enterolignan exposure was also found to be associated with reduced risk of breast cancer (5 studies, combined OR = 0.73, 95% CI: 0.57 - 0.92, P=0.009) but the study results were inconsistent. No association was found between blood enterolactone levels and risk of breast cancer (combined OR = 0.82, 95% CI: 0.59 - 1.14, P=0.24). The authors conclude that plant lignans may be associated with a small reduction in post-menopausal breast cancer risk, but that further studies are required to confirm these results.

The current nested case-control study was designed to investigate the association between enterolactone concentration and breast cancer risk and if this association differs depending on the estrogen receptor (i.e., ERα) and ERβ status of the tumors. Differences in the estrogen receptor status of tumors may help explain contradictions in epidemiologic studies that examined the associations between plasma concentrations of enterolactone and breast cancer. The study included 366 cases and 733 matched controls within the Malmö Diet and Cancer cohort. A modified diet history was used to determine dietary habits. Dietary fiber, fruits and berries, and high-fiber bread each were found to have statistically significant positive correlations with enterolactone whereas smoking and obesity were associated with lower enterolactone concentrations. Enterolactone concentrations above the median (16 nmol/L) were found to be associated with reduced breast cancer risk when compared with those below the median (odds ratio (OR) = 0.75, 95% confidence interval (95% CI) = 0.58-0.98). However, the reduced risk was observed only for ER+ (OR = 0.73, 95% CI = 0.55-0.97) and ERβ– (OR = 0.60, 95% CI = 0.42-0.84) tumors, with significantly different risks for ERβ– and ERβ+ tumors (P for heterogeneity = 0.04). The authors conclude that the protective association between enterolactone and breast cancer is significantly different between ERβ– and ERβ+ tumors and most evident in tumors that express ER but not ERβ.

The current prospective study examined the associations between the risk of invasive breast cancer in postmenopausal women and dietary intakes of four plant lignans (pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol) and estimated exposure to two enterolignans (enterodiol and enterolactone). The study included 58,049 postmenopausal French women who were not taking soy isoflavone supplements. The women completed a self-administered diet history questionnaire. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazards regression models. Analyses were stratified by tumor combined estrogen and progesterone receptor (ER/PR) status. During a median follow-up period of 7.7 years, 1,469 cases of breast cancer were diagnosed. Women in the highest quartile of total lignan intake (greater than 1,395 µg per day) were found to have a reduced risk of breast cancer (RR = 0.83, 95% CI = 0.71-0.95, Ptrend = .02) compared to women in the lowest quartiles, as did those in the highest quartile of lariciresinol intake (RR = 0.82, 95% CI = 0.71-0.95, Ptrend = .01). The inverse associations between phytoestrogen intakes and postmenopausal breast cancer risk were restricted to ER+ and PR+ disease (RR for highest versus lowest quartiles of total plant lignan intake = 0.72, 95% CI = 0.58 - 0.88, Ptrend = .01). The authors conclude that high dietary intakes of plant lignans and high exposure to enterolignans are associated with reduced risks of ER+/PR+ postmenopausal breast cancer in a Western population that does not consume a diet rich in soy.

The present European nested case-control prospective study was designed to examine the association between plasma phytoestrogen levels and breast cancer risk. Study participants were drawn from the Prospect cohort, a Dutch cohort participating in the European Prospective Investigation into Cancer and Nutrition. The study included 383 breast cancer cases, of whom 87 were premenopausal or perimenopausal women with average age of 52 years, and 296 postmenopausal women with average age of 59 years, all matched to controls. Plasma levels of isoflavones (daidzein, genistein, glycitein, O-desmethylangolensin, and equol) and lignans (enterodiol and enterolactone) were assessed. Breast cancer odds ratios (ORs) were calculated for tertiles of phytoestrogen plasma levels with conditional logistic regression analysis. For genistein, the risk estimate for the highest versus the lowest tertile indicated a protective effect against breast cancer risk, OR = 0.68 (95% CI, 0.47-0.98). The ORs for the other isoflavones showed similar, though not statistically significant, protective effects. Lignan levels were not found to be associated with breast cancer risk. The results did not differ by menopausal status. The authors conclude that high circulating genistein levels are associated with reduced breast cancer risk in the Dutch population.

The present study was designed to examine the impact of maternal dietary exposure to fiber during pregnancy on the female offsprings' later susceptibility to developing breast cancer. Pregnant rats were fed diets containing 6% fiber originating either from cellulose (control), oat, whole wheat, or defatted flax flour. Mammary tumors were induced in the offspring by administering the carcinogen 7,12-dimethylbenz[a]anthracene at the age of 50 days. Tumor incidence and multiplicity were found to be reduced in the whole wheat flour-exposed offspring and increased in the defatted flax-exposed offspring. To identify the mechanisms involved, changes in mammary gland morphology and gene expression were assessed before the onset of puberty (age three weeks) and at eight weeks, the age at which rats are most susceptible to malignant transformation. The number of terminal end buds (i.e., the targets of malignant transformation) was found to be lower in the mammary glands of whole wheat flour-exposed and oat flour-exposed offspring compared to the controls. In addition, the number of apoptotic epithelial cells was found to be elevated in the whole wheat flour offspring, but no changes in cell proliferation, estrogen receptor alpha, or cyclin D1 mRNA or protein levels were observed. The mRNA and/or protein levels of BRCA1 and p53 were significantly higher in the mammary glands of the whole wheat flour offspring. Furthermore, the levels of 8-hydroxy-2'-deoxyguanosine, a marker of DNA damage, were significantly reduced in these rats. This suggests that maternal dietary exposure to whole wheat during pregnancy may reduce offspring's breast cancer risk by enhancing DNA damage repair mechanisms.

The present German case-control study of breast cancer by age 50 was designed to evaluate the association between dietary intake of various phytoestrogens and premenopausal breast cancer risk. A diet high in isoflavonoids (soy) has been found to be associated with lower breast cancer risk in among Asians. However, since soy intake is relatively low in Western populations, dietary lignans may be the more important phytoestrogen class in these women. In the study, diet-related data was collected from 278 premenopausal breast cancer cases and 666 age-matched controls using a validated food frequency questionnaire. Using multivariate logistic regression, the highest vs. lowest intake quartiles of dietary daidzein and genistein intake resulted in significantly reduced odds ratios (ORs) (95% CI) for breast cancer risk of 0.62 (0.40–0.95) and 0.47 (0.29–0.74), respectively. The protective effects of daidzein and genistein were found to be associated with hormone receptor-positive tumors. High intake of other isoflavonoids such as formononetin and biochanin A, as well as total isoflavonoids, were not associated with a decrease in breast cancer risk. High intake of the plant lignan matairesinol was associated with significantly reduced breast cancer risk (OR = 0.58, 95% CI 0.37–0.94), but lower risk was not associated with consumption of the lignan secoisolariciresinol or with the sum of plant lignans. However, the estimated intake of both mammalian lignans, enterodiol and enterolactone, were found to be inversely associated with breast cancer risk (ORs = 0.61 (0.39–0.98) and 0.57 (0.35– 0.92), respectively). No impact on risk was found for total phytoestrogen intake. The authors conclude that the dietary intake of daidzein and genistein may have an important role in reducing breast cancer risk despite low levels of intake, and matairesinol and mammalian lignans may also reduce breast cancer risk.