Effects of a phytoestrogen-containing soy extract on the growth-inhibitory activity of ICI 182 780 in an experimental model of estrogen-dependent breast cancer

Abstract

The study reported here was designed to determine whether a phytoestrogen-containing soy extract (SSE) could negate/overwhelm the inhibitory effects of ICI 182 780 on the growth of estrogen-sustained human breast cancer xenografts (MCF-7), in ovariectomized athymic mice. As expected, estradiol-supplemented tumors did not grow over the study period in ICI 182 780-treated females; concomitant administration of 50 mg/kg per day SSE slightly potentiated the inhibitory activity of the drug, while at 100 mg/kg per day, SSE partially negated ICI 182 780 activity. In keeping with these in vivo outcomes, we observed that the level of cyclin D1 (and progesterone receptor) in MCF-7 xenografts was considerably reduced by ICI 182 780, an effect enhanced by concomitant treatment with 50 SSE, but reduced by the higher dosage (i.e. 100 mg/kg per day). Thrombospondin-1 (TSP-1) and kallikrein 6 (KLK6) levels were also reduced following ICI 182 780, although to a lesser degree; again, combined anti-estrogen and SSE produced a dose-dependent regulation in TSP-1 and KLK6 tumor level, with a further reduction in the mRNA gene expression at 50 SSE (compared with ICI 182 780) and a partial reversion of the drug-induced down-regulation at 100 mg/kg per day. No modulation was detected in the serum concentration of IGF-1 (a potent mitogen for estrogen receptor-positive breast cancer cell lines) either upon treatment with ICI 182 780 or concomitant administration of the anti-estrogen with SSE. In conclusion, results from this study raise concerns about the consumption of isoflavone supplements in conjunction with ICI 182 780 therapy, in postmenopausal women with estrogendependent breast cancer.

Soy Phytochemicals Decrease Nonsmall Cell Lung Cancer Growth In Female Athymic Mice3

“…Finally, results obtained in this study did not show any modulation of IGF-I serum levels upon administration of SSE, a finding in keeping with previous results by our and other groups in preclinical models of estrogen-dependent breast cancer (28,29) but inconsistent with other literature data showing a reduction in circulating levels of this growth factor in mice bearing human prostate or bladder tumors following consumption of dietary soy products (30,31). The reason why effects of soy isoflavones on IGF-I signaling are seen in some experimental systems but not in others is not understood, possibly involving differences in both cell lines and/or experimental conditions.…”

Soy Isoflavones in Nutritionally Relevant Amounts Have Varied Nutrigenomic Effects on Adipose Tissue

“…A soybean purified extract containing isoflavones glycosides genistein and daidzein (14.7%; Soyselect ® ), was kindly donated by Indena (Milan, Italy). Soyselect ® is a standardized extract obtained from soy with a double standardization procedure and which contains 13%–17% of isoflavone glycosides genistein and daidzein and <18% of B-group saponins, as quantified by HPLC [ 34 , 35 ]. The product is prepared by extracting ripe whole soy beans or oil-free soy flour with aliphatic alcohols through an industrial manufacturing proprietary process [ 36 , 37 ].…”

The impact of xenoestrogens on effectiveness of treatment for hormone-dependent breast cancer – current state of knowledge and perspectives for research

“…Gallo et al [53] studied the effect of soy extract, standardized on the content of genistein and daidzein, on the action of fulvestrant, which inhibited the formation of breast cancer in ovariectomized mice. Low doses of phytoestrogens -50 mg soy extract/kg bw/day, have been shown to slightly increase the inhibitory effect of fulvestrant, while higher doses -100 mg soy extract/kg bw/day significantly reduced the antitumour activity of the drug [53].…”

“…Gallo et al [53] studied the effect of soy extract, standardized on the content of genistein and daidzein, on the action of fulvestrant, which inhibited the formation of breast cancer in ovariectomized mice. Low doses of phytoestrogens -50 mg soy extract/kg bw/day, have been shown to slightly increase the inhibitory effect of fulvestrant, while higher doses -100 mg soy extract/kg bw/day significantly reduced the antitumour activity of the drug [53]. In contrast, the lack of interaction between fulvestrant and genistein was indicated by the results of experiments by Dess et al [54], who showed that low doses of genistein (1µM) and zearalenone (1nM), similar to the pesticide DDT (dichlorodiphenyltrichloroethane known for breast cancer proliferation promoting properties), increase the activity of cyclin-dependent kinase 2 (Cdk2), synthesis of cyclin D1 and hyperphosphorylation of pRbl05 (retinoblastoma protein) in MCF-7 cells.…”