Physiological Concentrations of Dietary Genistein Dose-Dependently Stimulate Growth of Estrogen-Dependent Human Breast Cancer (MCF-7) Tumors Implanted in Athymic Nude Mice

Abstract

Previously our laboratory has shown that the soy isoflavone, genistein, stimulates growth of human breast cancer (MCF-7) cells in vivo and in vitro. In this study, the dose-response analysis of genistein at the physiologically achievable concentration range between 125 and 1,000 microg/g in the diet was conducted in ovariectomized athymic nude mice implanted with MCF-7 cells. We hypothesized that genistein at this concentration range can stimulate dose-dependently the breast tumor growth, cell proliferation and an estrogen-responsive pS2 gene induction. Tumor size and body weight were monitored weekly. At completion of the study, we analyzed cellular proliferation of tumors using incorporation of BrdU, pS2 expression of tumors using a Northern blot analysis and total genistein level in plasma using liquid chromatography-isotope dilution mass spectrometry (LC-ES/MS). Dietary genistein (> or = 250 microg/g) increased tumor size in a dose-dependent manner [8.4x the negative control (NC) group in the 250 microg/g group, 12.0x in the 500 microg/g group, 20.2x in the 1,000 microg/g group and 23.2x in the positive control (PC) group]. The percentage of proliferating cells was significantly increased by genistein at and above 250 microg/g (5.3x the NC group in the 250 microg/g, 5.6x in the 500 microg/g, 5.0x in the 1,000 microg/g and 4.8x in the PC group). Expression of pS2 mRNA was also significantly increased with increasing dietary genistein levels (11.25x the NC group in the 500 microg/g group and 15.84x in the 1,000 microg/g group). Total plasma genistein concentrations were between 0.39 and 3.36 micromol/L in mice fed between 125 and 1,000 microg/g genistein. In conclusion, dietary treatment with genistein at physiological concentrations produces blood levels of genistein sufficient to stimulate estrogenic effects, such as breast tumor growth, cellular proliferation and pS2 expression in athymic mice in a dose-responsive manner similar to that seen in vitro.

Mammalian lignans enterolactone and enterodiol, alone and in combination with the isoflavone genistein, do not promote the growth of MCF‐7 xenografts in ovariectomized athymic nude mice

“…This suggests a weak estrogenic effect of GEN, which was further indicated by the significant increase in tumor cell proliferation. This estrogen-like activity of GEN on breast cancer xenografts has also been indicated in previous in vivo studies, 17,19 in which GEN induced MCF-7 tumor growth and cell proliferation.…”

“…The study design was similar to our previous work 14 and those of others, 17,19 which used ovariectomized athymic mice as a model mimicking postmenopausal situation. Briefly, after 7-day acclimatization while being fed the BD, mice were anesthetized with ketamine/zylazine mixture and implanted with a sterilized l7b-estradiol (E2) pellet (1.7 mg, 60 day release; produce 3.0-4.0 nmol/L E2 blood level; Innovative Research of America, Sarasota, FL).…”

“…Both ENL and GEN induced estrogenic effects on MCF-7 cells in vitro, 15,16 however, it is unknown if the mammalian lignans will act estrogenically and stimulate the growth of MCF-7 tumors in vivo as previously observed with GEN. 17 Furthermore, the effect of these phytoestrogens in combination, at the same concentration as each phytoestrogen alone, has not been studied. Thus, the primary objective of this study was to determine the effects of the mammalian lignans, ENL and END, alone and in combination with the isoflavone GEN, on the growth of human MCF-7 breast cancer xenografts.…”

Genistein inhibits Brca1 mutant tumor growth through activation of DNA damage checkpoints, cell cycle arrest, and mitotic catastrophe

“…18 However, genistein exposure was found to stimulate the growth of MCF-7 cells injected into the ovariectomized nude mice model. 29 The DMBA-induced breast cancer mice also showed a shortened latent period and increased cancer incidence depending on the ER a allele. 30 The discrepancy among different studies could be caused by multiple factors, such as different characteristics of tumor models, different dosages of genistein, and different timings of drug exposure.…”

Flaxseed attenuates the tumor growth stimulating effect of soy protein in ovariectomized athymic mice with MCF‐7 human breast cancer xenografts

“…7,8 Isoflavone and lignan-rich diets are reported to have distinct effects on the growth of estrogen responsive tumors in vivo. After estrogen deprivation, SP and its isoflavone genistein have been shown to increase the growth of the MCF-7 tumors in ovariectomized animals, [9][10][11] while no stimulation of MCF-7 tumor growth has been observed when mice were exposed to FS 12 or its mammalian lignan metabolites, enterodiol and enterolactone. 11 In addition, FS, SDG and enterolactone have been shown to reduce the growth of the dimethylbenzanthracene (DMBA)-induced hormone responsive mammary tumors in nonovariectomized rats, [13][14][15] suggesting a protective role of lignan-rich diets and enterolactone in breast cancer.…”