Effects of the Phytoestrogens Genistein and Daidzein on BRCA2 Tumor Suppressor Gene Expression in Breast Cell Lines

Vissac-Sabatier, Cécile; Bignon, Yves‐Jean; Bernard‐Gallon, Dominique

doi:10.1207/s15327914nc4502_15

Cited by 41 publications

(20 citation statements)

References 30 publications

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“…As reported (26), genistein only inhibits PTK at a much higher concentration (100 mol/l). In addition, daidzein, an analog of genistein that does not inhibit PTK, also significantly increased insulin secretion and stimulated PKA activity, although these effects are less potent than those of genistein as previously observed in other tissues (27), further supporting a PTK-independent effect of genistein. Additionally, these results suggest that genistein should be cautiously used in studies of PTK signal transduction, because increased activation of PKA by genistein may contribute to the observed effects.…”

Section: Discussionsupporting

confidence: 66%

Genistein Acutely Stimulates Insulin Secretion in Pancreatic β-Cells Through a cAMP-Dependent Protein Kinase Pathway

et al. 2006

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Although genistein, a soy isoflavone, has beneficial effects on various tissues, it is unclear whether it plays a role in physiological insulin secretion. Here, we present evidence that genistein increases rapid glucose-stimulated insulin secretion (GSIS) in both insulin-secreting cell lines (INS-1 and MIN6) and mouse pancreatic islets. Genistein elicited a significant effect at a concentration as low as 10 nmol/l with a maximal effect at 5 mol/l. The effect of genistein on GSIS was not dependent on estrogen receptor and also not related to an inhibition of protein tyrosine kinase (PTK). Consistent with its effect on GSIS, genistein increases intracellular cAMP and activates protein kinase A (PKA) in both cell lines and the islets by a mechanism that does not involve estrogen receptor or PTK. The induced cAMP by genistein, at physiological concentrations, may result primarily from enhanced adenylate cyclase activity. Pharmacological or molecular intervention of PKA activation indicated that the insulinotropic effect of genistein is primarily mediated through PKA. These findings demonstrated that genistein directly acts on pancreatic ␤-cells, leading to activation of the cAMP/PKA signaling cascade to exert an insulinotropic effect, thereby providing a novel role of soy isoflavones in the regulation of insulin secretion. Diabetes 55:1043-1050, 2006 S oy isoflavones have received widespread attention over the past few years because of their potential for preventing some highly prevalent chronic diseases. Genistein, the primary soy-derived isoflavone, has various biological actions, including a weak estrogenic effect by binding to estrogen receptors (1) and inhibiting protein tyrosine kinases (PTKs) (2). Studies on whether genistein has an effect on diabetes are very limited. Recent studies performed in animals and humans have shown that ingestion of soy protein associated with isoflavones moderates hyperglycemia (3,4), suggesting a beneficial role for soy in diabetes. However, it is not clear whether the beneficial effect of soy protein is due to genistein or other components. Data from recent animal studies suggest an antidiabetic effect of genistein presumably by a hypolipidemic effect (5). However, recent reports demonstrated that soy isoflavone administration lowered plasma glucose, whereas triglyceride levels were unaffected in obese and diabetic animals (6) and postmenopausal women (7). Therefore, although these data suggest that genistein may have a protective role in diabetes, the mechanism underlying these beneficial effects is still largely unknown.Few data exist on whether genistein has a direct effect on pancreatic ␤-cells. Several earlier studies demonstrated that genistein stimulates insulin secretion from a clonal pancreatic ␤-cell line (8) and cultured islets (9,10), whereas other studies have found an inhibitory effect on insulin secretion (11,12). These discrepant data may be the result of variations in the experimental conditions and model used. Nevertheless, the doses used in most of these studi...

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Section: Discussionsupporting

confidence: 66%

Genistein Acutely Stimulates Insulin Secretion in Pancreatic β-Cells Through a cAMP-Dependent Protein Kinase Pathway

et al. 2006

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“…Our findings indicate that genistein upregulates BRCA1 and BRCA2 expression in breast and prostate cancer cell lines. In a previous study, genistein caused an increase in BRCA2 mRNA (but not protein) levels in MDA-MB-231 and MCF-10A but not in MCF-7 cells (Vissac-Sabatier et al, 2003). In that study, daidzein, another soy isoflavone, had no effect on BRCA2 expression.…”

Section: Discussionmentioning

confidence: 65%

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

et al. 2006

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Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-a) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time-and dosedependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 mM) and genistein (0.5 -1.0 mM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-a activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.

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“…In immortalized human breast epithelial cells, genistein inhibited cell proliferation by down-regulating expression of the MET protooncogene and up-regulating that of the tumor suppressor gene EGR1 as well as that of the immediate-early response genes FOS and JUN [30]. The inhibition by genistein of the growth of human breast tumor cells derived from an invasive carcinoma was associated with a marked increase in BRCA2 expression [31]. Collectively, these observations indicate that up-regulation of the expression of tumor suppressor genes by flavone or flavonoids is a contributing factor to their antitumoral activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

Ullmannova

Popescu

2007

Cancer Detection and Prevention

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Background-Dietary flavone was previously shown to increase the expression of deleted in liver cancer-1 gene (DLC-1) in HT-29 colon carcinoma cell line (Proteomics 2004;4:2455-64). DLC-1 that encodes a Rho GTPase-activating protein, functions as a tumor suppressor gene and is frequently inactivated or down-regulated in several common cancers. Restoration of DLC-1 expression suppresses in vitro tumor cells proliferation and tumorigenicity in vivo.Methods-Here, the effect of flavone was examined in several DLC-1-deficient cell lines derived from different types human cancer using assays for cell proliferation, gene expression and transfer.Results-We show that exposure to 15μM flavone increased DLC1 expression in breast but not in liver or prostate carcinoma cells or a nonmalignant breast epithelial cell line. Flavone restored the expression of DLC1 in the breast carcinoma cell lines MDA-MB-468, MDA-MB-361, and BT20 as well as in the colon carcinoma cell line HT-29 all of which are DLC-1-negative due to promoter hypermethylation. We further show that flavone inhibited cell proliferation, induced cell cycle arrest at G2-M, increased p21 Waf1 gene expression, and caused apoptosis. Microarray analysis of these aggressive and metastatic breast carcinoma cells revealed 29 flavone-responsive genes, among which the DNA damage-inducible GADD genes were up-regulated and the proto-oncogene STMN1 and IGFBP3 were down-regulated.Conclusions-Flavone-mediated alterations of genes that regulate tumor cell proliferation, cell cycle, and apoptosis contribute to chemopreventive and antitumoral effects of flavone. Alone or in combination with demethylating agents, flavone may be an effective adjunct to chemotherapy in preventing breast cancer metastasis.

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Effects of the Phytoestrogens Genistein and Daidzein on BRCA2 Tumor Suppressor Gene Expression in Breast Cell Lines

Cited by 41 publications

References 30 publications

Genistein Acutely Stimulates Insulin Secretion in Pancreatic β-Cells Through a cAMP-Dependent Protein Kinase Pathway

Genistein Acutely Stimulates Insulin Secretion in Pancreatic β-Cells Through a cAMP-Dependent Protein Kinase Pathway

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

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