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The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being the inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/d as the purified soy extract G-2535) for 14 to 21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age, 71 years). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects' but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (P = 0.07). This difference was most prominent when comparing the 300-mg group with placebo (P = 0.015), but there was no significant reduction in p-EGFR staining between the 600-mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups were observed for COX-2, Ki-67, activated caspase-3, Akt, p-Akt, mitogen-activated protein kinase (MAPK), or p-MAPK. No significant differences in urinary survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents., (2012 AACR)

Background: Although several epidemiologic studies have found that isoflavone intake assessed by questionnaire is associated with a decreased risk of lung cancer, no prospective study has investigated this association using blood concentrations of isoflavones., Methods: We conducted a nested case-control study within a population-based prospective cohort study. A total of 24,127 women aged 40 to 69 years who returned the baseline questionnaire and provided blood samples were observed from 1990 through 2006. During a median follow-up period of 13.5 years, 126 newly diagnosed lung cancer cases were identified. For each case, we selected two controls matched for age, area, smoking status, and condition of blood draw. A conditional logistic regression model was used to estimate the odds ratios (ORs) and 95% CIs of lung cancer in relation to plasma concentrations of genistein, daidzein, glycitein, equol, and total isoflavones., Results: After exclusion of 20 lung cancer cases diagnosed in the first 3 years after blood collection, an inverse association was found between plasma genistein concentration and lung cancer risk. The multivariate-adjusted OR (95% CI) of lung cancer in the highest quintile of plasma genistein concentration as compared with that in the lowest quintile was 0.31 (0.12, 0.86; P for trend=0.085). Other isoflavones and total isoflavones were not associated with a significant decrease in the risk of lung cancer., Conclusion: Plasma genistein concentration was inversely associated with lung cancer risk in Japanese women., Impact: Our data support the previously observed association between isoflavone intake and lung cancer risk., (©2011 AACR.)

Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in >80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 MAPK, and HSP27 "promotility" proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way.

Background: Proliferative benign breast conditions are associated with elevated risk of breast cancer, whereas nonproliferative conditions are not strongly associated with risk. Factors acting before onset of hyperplasia might be associated with both benign conditions and breast cancer, whereas those on the proliferative disease-to-cancer pathway would be associated only with cancer. Soy isoflavone exposure may influence breast cancer risk, but little is known of its association with benign conditions., Materials and Methods: We examined possible relationships between plasma genistein and daidzein concentrations and risk of breast disease in women, in a breast self-examination trial in Shanghai, China, diagnosed with breast cancer (n = 196) or a benign breast condition (n = 304), and 1,002 age-matched controls with no known breast disease. Benign conditions were classified as nonproliferative (n = 131) or proliferative with or without atypia (n = 173)., Results: Isoflavone concentrations were inversely associated with risk of nonproliferative and proliferative benign fibrocystic conditions, as well as with breast cancer, both with and without concomitant proliferative changes in ipsilateral noncancerous mammary epithelium (P(trend) < 0.01 for all comparisons with controls). Women in the highest quartile of plasma genistein (>76.95 ng/mL) were less likely to have breast cancer (odds ratio, 0.26; 95% confidence interval, 0.13-0.50) or benign conditions (odds ratio, 0.40; 95% confidence interval, 0.23-0.70) compared with women in the lowest quartile (<9.42 ng/mL). Observed risks for breast cancer with and without surrounding proliferative changes were not different, respectively, from observed risks for benign proliferative and nonproliferative conditions alone., Conclusion: Isoflavone exposure was inversely associated with fibrocystic breast conditions and breast cancer, and the results suggest that effects on cancer risk occur early in carcinogenesis.

The use of dietary isoflavone supplements by postmenopausal women with breast cancer is increasing. We investigated interactions between the soy isoflavone, genistein, and an antiestrogen, tamoxifen (TAM), on the growth of estrogen (E)-dependent breast cancer (MCF-7) cells implanted in ovariectomized athymic mice. We hypothesized that weakly estrogenic genistein negate/overwhelm the inhibitory effect of TAM on the growth of E-dependent breast tumors. Six treatment groups were used: control (C); 0.25 mg estradiol (E2) implant (E); E2 implant + 2.5 mg TAM implant (2.5 TE); E2 implant + 2.5 mg TAM implant + 1000 ppm genistein (2.5 TEG); E2 implant + 5 mg TAM implant (5 TE), and E2 implant +5 mg TAM implant +1000 ppm genistein (5 TEG). Treatment with TAM (2.5 TE and 5 TE) suppressed E2-stimulated MCF-7 tumor growth in ovariectomized athymic mice. Dietary genistein negated/overwhelmed the inhibitory effect of TAM on MCF-7 tumor growth, lowered E2 level in plasma, and increased expression of E-responsive genes (e.g., pS2, PR, and cyclin D1). Therefore, caution is warranted for postmenopausal women consuming dietary genistein while on TAM therapy for E-responsive breast cancer.

Phytoestrogens are plant-derived compounds that may have cancer-protective properties. The purpose of the study was to see how enterolactone, daidzein, and genistein serum concentrations reflect major changes in the diet of Finnish subjects. Phytoestrogen concentrations were measured by time-resolved fluoroimmunoassay after hydrolysis and extraction in samples from 85 middle-aged subjects who were part of a 12-week dietary intervention study carried out in North Karelia, Finland. In the baseline and the switchback periods, the subjects consumed their habitual Finnish diet, which is high in saturated fat and low in polyunsaturated fat and vegetables. During the 12-week intervention period, the proportion of dietary energy derived from fat was reduced from approximately 39% to 23%, and the consumption of vegetables, fruit, and berries was markedly increased. Enterolactone concentrations were measured during the baseline, intervention, and switchback periods. The median concentration of enterolactone rose from 12.2 to 19.5 nmol/l (P = 0.002) during the low-fat, high-vegetable diet. Daidzein and genistein concentrations were very low and did not change during the intervention. At baseline, 65% of the population had a low serum enterolactone concentration of <15 nmol/l. During the intervention period, this proportion fell to 34%. These major differences in serum enterolactone concentrations suggest that enterolactone may be used as a biomarker of a healthy diet containing plenty of vegetables, fruit, and berries.

Ovarian hormones are biomarkers for breast cancer risk. Soybean consumption may be responsible in part for lower levels of ovarian hormones and decreased rates of breast cancer in women in Asia compared with Western populations. Soybeans contain a significant amount of the isoflavones daidzein and genistein, which are weak estrogens. The purpose of this study was to determine whether soya feeding decreases circulating levels of ovarian hormones and gonadotropins. Ten healthy, regularly cycling women consumed a constant soya-containing diet on a metabolic unit, starting on day 2 of a menstrual cycle until day 2 of the next cycle. Blood and urine samples were obtained daily for one menstrual cycle before and during soy feeding. The diet was calculated to maintain constant body weight, included 400 kilocalories from a 36-ounce portion of soymilk, and provided 113-207 mg/day (154.0+/-8.4 mg/day, mean +/- SE) of total isoflavones. For the group, the soya diet provided more carbohydrate and less protein than the home diets. Daily consumption of the soya diet reduced circulating levels of 17beta-estradiol by 25% (P<0.01, Wilcoxon signed rank test, two-tailed) and of progesterone by 45% (P<0.0001) compared with levels during the home diet period but had no effect on luteinizing hormone or follicle-stimulating hormone. Mean menstrual cycle length did not change during the soya diet; a slight decrease in mean luteal cycle length was marginally statistically significant (P = 0.06). Urinary excretion of isoflavones was 33.8+/-5.3 mg/day (mean +/- SE) and when expressed as percentage of intake, varied substantially (21.9+/-3.3% of intake; range, 9.1-36.7%) among the subjects. Mean daily serum levels of daidzein and genistein (free and conjugated forms) 15 h after soymilk were 2.89+/-0.53 microg/ml and 0.85+/-0.22 microg/ml, respectively, indicating systemic bioavailability of these substances. Secondary analyses by multiple regression showed that decreases in follicular and luteal phase 17beta-estradiol levels were positively associated with urinary isoflavone excretion, an association affected by age, and were inversely associated with decreases in protein intake. Decreases in progesterone levels during the soya diet were inversely associated with increases in intakes of genistein and were affected by the interaction of the intakes of daidzein with energy or with fiber. Consumption of an isoflavone-containing soya diet reduced levels of ovarian steroids in normal women over the entire menstrual cycle without affecting gonadotropins. This suggests that at least under the conditions of this study, soya-induced reductions of circulating ovarian steroids are not mediated by gonadotropins. Decreases in ovarian hormones are related to isoflavones contained in soy and also to energy intake and other components such as protein and fiber but not fat. Our results may explain decreased ovarian hormone levels and decreased risk of breast cancer in populations consuming soya diets and have implications for reducing breast cancer risk by dietary intervention.

We examined the distribution and long-term reliability of serum measurements of the two main human lignans, enterolactone and enterodiol, and the isoflavonoid phytoestrogens daidzein, genistein, equol, and O-Desmethylangolensin in the New York University Women's Health Study, a prospective cohort study of sex hormones and breast cancer. Serum samples collected at three yearly visits in 30 premenopausal and 30 postmenopausal women who had not been diagnosed with cancer or cardiovascular disease were included in the study. Assays were carried out by ion-exchange chromatography and capillary gas chromatography-mass spectrometry. Levels of isoflavonoid phytoestrogens were low, often at or below the sensitivity level of the assay. The reliability coefficients for these compounds were also low (< or =0.30). The median levels of enterodiol and enterolactone were 1.52 nmol/liter and 20.2 nmol/liter, respectively, and were comparable with the levels observed in omnivorous Finnish women living in the Helsinki area. A substantial number of women, though, had fairly high levels: for instance, 15% of the assays showed levels of enterolactone greater than the mean level observed in vegetarian Finnish women, i.e., 89.1 nmol/liter (H. Adlercreutz et al., Cancer Detec. Prev., 18: 259-271, 1994). The reliability coefficient of a single measurement of enterolactone was moderately high (0.55), suggesting that serum measurements of this compound could be a useful tool in prospective epidemiological studies with access to repeated blood or serum specimens. For instance, the reliability coefficient of the average of three measurements of enterolactone would be 0.79, a level considered acceptable in light of the other sources of error that are present in epidemiological studies (W. Willett, Stat. Med., 8: 1031-1040, 1989).

Genistein, found in soy products, is a phytochemical with several biological activities. In the current study, our research focused on the estrogenic and proliferation-inducing activity of genistein. We have demonstrated that genistein enhanced the proliferation of estrogen-dependent human breast cancer (MCF-7) cells in vitro at concentrations as low as 10 nM, with a concentration of 100 nM achieving proliferative effects similar to those of 1 nM estradiol. Expression of the estrogen-responsive gene pS2 was also induced in MCF-7 cells in response to treatment with a concentration of genistein as low as 1 microM. At higher concentrations (above 20 microM), genistein inhibits MCF-7 cell growth. In vivo, we have shown that dietary treatment with genistein (750 ppm) for 5 days enhanced mammary gland growth in 28-day-old ovariectomized athymic mice, indicating that genistein acts as an estrogen in normal mammary tissue. To evaluate whether the estrogenic effects observed in vitro with MCF-7 cells could be reproduced in vivo, MCF-7 cells were implanted s.c. in ovariectomized athymic mice, and the growth of the estrogen-dependent tumors was measured weekly. Negative control animals received the American Institute of Nutrition (AIN)-93G diet, the positive control group received a new s.c. estradiol (2 mg) pellet plus the AIN-93G diet, and the third group received genistein at 750 ppm in the AIN-93G diet. Tumors were larger in the genistein (750 ppm)-treated group than they were in the negative control group, demonstrating that dietary genistein was able to enhance the growth of MCF-7 cell tumors in vivo. Increased uterine weights were also observed in the genistein-treated groups. In summary, genistein can act as an estrogen agonist in vivo and in vitro, resulting in the proliferation of cultured human breast cancer cells (MCF-7) and the induction of pS2 gene expression. Here we present new information that dietary genistein stimulates mammary gland growth and enhances the growth of MCF-7 cell tumors in ovariectomized athymic mice.