The potential benefit of soy isoflavones in breast cancer chemoprevention, as suggested by epidemiological studies, has aroused the interest of numerous scientists for over twenty years. Although intensive work has been done in this field, the preclinical results continue to be controversial and the molecular mechanisms are far from being fully understood. The antiproliferative effect of soy isoflavones has been commonly linked to the estrogen receptor interaction, but there is growing evidence that other pathways are influenced as well. Among these, the regulation of apoptosis, cell proliferation and survival, inhibition of angiogenesis and metastasis or antioxidant properties have been recently explored using various isoflavone doses and various breast cancer cells. In this review, we offer a comprehensive perspective on the molecular mechanisms of isoflavones observed in in vitro studies, emphasizing each time the dose-effect relationship and estrogen receptor status of the cells. Furthermore, we present future research directions in this field which could provide a better understanding of the inner molecular mechanisms of soy isoflavones in breast cancer.

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Soy Isoflavones and Breast Cancer Cell Lines: Molecular Mechanisms and Future Perspectives

The potential “health benefits” of dietary polyphenols have been ascribed to their direct antioxidant activity and their impact on the regulation of cell and tissue redox balance. However, because of the relative poor bioavailability of many of these compounds, their effects could not be easily explained by the antioxidant action, which may occur only at high circulating and tissue concentrations. Therefore, many efforts have been put forward to clarify the molecular mechanisms underlining the biological effect of polyphenols in physiological and pathological conditions. Polyphenols’ bioavailability, metabolism, and their effects on enzyme, membrane, and/or nuclear receptors and intracellular transduction mechanisms may define the overall impact of these compounds on cancer risk and progression, which is still debated and not yet clarified. Polyphenols are able to bind to estrogen receptor α (ERα) and β (ERβ), and therefore induce biological effects in human cells through mimicking or inhibiting the action of endogenous estrogens, even at low concentrations. In this work, the role and effects of food-contained polyphenols in hormone-related cancers will be reviewed, mainly focusing on the different polyphenols’ mechanisms of action with particular attention on their estrogen receptor-based effects, and on the consequences of such processes on tumor progression and development.

Beyond the Antioxidant Activity of Dietary Polyphenols in Cancer: the Modulation of Estrogen Receptors (ERs) Signaling.

Role of dietary bioactive natural products in estrogen receptor-positive breast cancer.

Phytoestrogens are a group of plant-derived compounds with an estrogen-like activity. In mammalians, phytoestrogens bind to the estrogen receptor (ER) and participate in the regulation of cell growth and gene transcription. There are several reports of the cytotoxic effects of phytoestrogens in different cancer cell lines. The aim of this study was to measure the phytoestrogen activity against breast cancer cells with different levels of ER expression and to elucidate the molecular pathways regulated by the leader compound. Methods used in the study include immunoblotting, transfection with a luciferase reporter vector, and a MTT test. We demonstrated the absence of a significant difference between ER+ and ER- breast cancer cell lines in their response to cytotoxic stimuli: treatment with high doses of phytoestrogens (apigenin, genistein, quercetin, naringenin) had the same efficiency in ER-positive and ER-negative cells. Incubation of breast cancer cells with apigenin revealed the highest cytotoxicity of this compound; on the contrary, naringenin treatment resulted in a low cytotoxic activity. It was shown that high doses of apigenin (50 μM) do not display estrogen-like activity and can suppress ER activation by 17β-estradiol. Cultivation of HER2-positive breast cancer SKBR3 cells in the presence of apigenin resulted in a decrease in HER2/neu expression, accompanied by cleavage of an apoptosis substrate PARP. Therefore, the cytotoxic effects of phytoestrogens are not associated with the steroid receptors of breast cancer cells. Apigenin was found to be the most effective phytoestrogen that strongly inhibits the growth of breast cancer cells, including HER2-positive ones.

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Apigenin Inhibits Growth of Breast Cancer Cells: The Role of ERα and HER2/neu.

Resveratrol and other dietary polyphenols are inhibitors of estrogen metabolism in human breast cancer cells.

Objective To explore the impact of lower concentrations of phytoestrogens on 17β-estradiol (E2) in the growth of MCF-7 breast cellsMethods MCF-7 cells were treated with E2 (10 − 8 mol/l), one of three phytoestrogens (genistein, resveratrol, and quercetin) (10 − 7  to 10 − 5 mol/l), and with a combination of both E2 and one of these phytoestrogens for 48 h These cells were then extracted for MTT and TUNEL assay Western blot was utilized to evaluate the proteins involved in the proliferative and apoptotic pathways, as well as the differential effects on ERα and βResults MCF-7 cell proliferations were induced by both E2 alone and E2 plus one of the three phytoestrogens (at concentrations ≥ 10 − 6 mol/l) Apoptotic cells were significantly increased in the phytoestrogen-treated MCF-7 cells and, conversely, suppressed in the cells treated with both E2 and phytoestrogens Proliferating cell nuclear antigen, PI3K and p-Akt were increased in the cultures with E2 and substantially more in the cultures 

M-h. Chien

Papers

Impact of lower concentrations of phytoestrogens on the effects of estradiol in breast cancer cells