Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells<i>in vitro</i>

Zava, David T.; Duwe, Gail

doi:10.1080/01635589709514498

Cited by 436 publications

(252 citation statements)

References 39 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…1,2 Genistein has been reported to have estrogenic properties and antineoplastic activity in multiple tumor types. 3 One mode by which hormonal agents work is by regulating gene activity by modulating epigenetic events such as histone acetylation and DNA methylation. 4,5 Genistein was also found to have epigenetic effects in the mouse prostate.…”

mentioning

confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

View full text Add to dashboard Cite

Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-jB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: genistein; prostate cancer; tumor suppressor gene Genistein (4 0 ,5,7-trihydroxyflavone), a naturally occurring isoflavenoid abundant in soy products, has been identified as an inhibitor of protein tyrosine kinases, which play key roles in cell growth and apoptosis. 1,2 Genistein has been reported to have estrogenic properties and antineoplastic activity in multiple tumor types. 3 One mode by which hormonal agents work is by regulating gene activity by modulating epigenetic events such as histone acetylation and DNA methylation. 4,5 Genistein was also found to have epigenetic effects in the mouse prostate. 6 Taken together, these findings suggest that genistein's antitumor activity may be mediated by epigenetic-based pathways. On the other hand, genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-jB) pathway, which could be mediated via AKT (AKT8 virus oncogene cellular homolog) signaling, the most important survival pathway in cellular signaling. 7 However, the precise molecular mechanism has yet to be characterized.AKT is a serine/threonine protein kinase functioning downstream of phosphatidylinositol 3-kinase (PI3K) in response to mitogen or growth factor stimulation. High-levels of AKT activation have been associated with the development and metastasis of several cancers. 8 AKT activation not only directly inhibits apoptosis by multiple mechanisms involved in inhibiting the conformational change of Bax, BAD and caspase-9 but also modulates apoptosis indirectly by influencing the activities of several transcription factors, including fork head transcription factors (FOXO) and...

show abstract

mentioning

confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

View full text Add to dashboard Cite

show abstract

“…The incidence of cancer increases when Asian women move to the United States, where the average diet is rich in fat and confers a strong significant protective effect during adolescence. Flavonoids and flavone exert a broad spectrum of biological effects by targeting genes involved in regulation of tumor cell proliferation, the cell cycle, and apoptosis, thus reducing the risk of cancer or inhibiting the growth of tumor cells [16,24,25,26,27]. Such effects were apparent in the present study.…”

Section: Discussionmentioning

confidence: 51%

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

View full text Add to dashboard Cite

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.

show abstract

“…Based on our cell growth experiments, an anti-oestrogenic activity, at least on oestrogen-and TGF-α-mediated cell stimulation, was shown for both compounds. Such effects were observed at concentrations of genistein likely to be locally found in breast tissue of subjects with a high dietary intake of soy (Zava and Duwe, 1997).…”

Section: Discussionmentioning

confidence: 88%

The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function

et al. 1999

View full text Add to dashboard Cite

We compared the oestrogenic and anti-oestrogenic properties of the two well-known phyto-oestrogens, genistein and quercetin, on the oestrogen-sensitive breast cancer cell line MCF-7. Genistein exerted a biphasic effect on growth of MCF-7 cells, stimulating at low and inhibiting at high concentrations, whereas quercetin was only growth inhibitory. At doses which did not inhibit cell growth, respectively 5 and 1 μ M , genistein and quercetin counteracted oestrogen- and transforming growth factor-α-promoted cell growth stimulation. Furthermore, genistein promoted transcription of the oestrogen-regulated genes pS2 and cathepsin-D, whereas quercetin interfered with the oestrogen-induced expression of the proteins. In in vitro binding experiments, genistein competed with oestradiol for binding to the oestrogen receptor (ER), but quercetin did not. Quercetin and genistein down-regulated cytoplasmic ER levels and promoted a tighter nuclear association of the ER, but only genistein was able to up-regulate progesterone receptor protein levels. In gel mobility assays, ER preincubation with oestradiol or with the two phyto-oestrogens led to the appearance of the same retarded band, excluding differences between the various complexes in binding to the consensus sequence. The data allowed us to conclude that quercetin acts like a pure anti-oestrogen, whereas genistein displays mixed agonist/antagonist properties, and to formulate a hypothesis on the possible mechanism of action of such phyto-oestrogens. © 1999 Cancer Research Campaign

show abstract

Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cellsin vitro

Cited by 436 publications

References 39 publications

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in 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

The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function

Contact Info

Product

Resources

About