Global gene expression profiles induced by phytoestrogens in human breast cancer cells

Dip, Ramiro; Lenz, Sarah; Antignac, Jean‐Philippe; Bizec, Bruno Le; Gmuender, Hans; Naegeli, Hanspeter

doi:10.1677/erc-07-0252

Cited by 49 publications

(39 citation statements)

References 55 publications

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“…Our BRET assay shows that genistein induces ER␣ homodimerization at 100 nM, a physiological concentration easily achievable by dietary intake (32)(33)(34)(35). Because ER␤ expression is lost in highly aggressive tumors, the concomitant activity of genistein to induce ER␣ homodimerization and subsequently activate ER␣-mediated transcription (36) may explain the failure of genistein in clinical trails for the treatment of breast cancer. On the contrary, liquiritigenin, an estrogenic compound tested in clinical trails, does not induce ER␣ homodimerization even at 1 M. Animal studies support the inability of liquiritigenin to stimulate xenograft tumor formation (28).…”

Section: Discussionmentioning

confidence: 88%

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Powell

2008

Proc. Natl. Acad. Sci. U.S.A.

101

119

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Estrogen receptor (ER) dimerization is prerequisite for its activation of target gene transcription. Because the two forms of ER, ER␣ and ER␤, exhibit opposing functions in cell proliferation, the ability of ligands to induce ER␣/␤ heterodimers vs. their respective homodimers is expected to have profound impacts on transcriptional outcomes and cellular growth. However, there is a lack of direct methods to monitor the formation of ER␣/␤ heterodimers in vivo and to distinguish the ability of estrogenic ligands to promote ER homo-vs. heterodimerization. Here, we describe bioluminescence resonance energy transfer (BRET) assays for monitoring the formation of ER␣/␤ heterodimers and their respective homodimers in live cells. We demonstrate that although both partners contribute to heterodimerization, ligand-bound ER␣ plays a dominant role. Furthermore, a bioactive component was found to induce ER␤/␤ homodimers, and ER␣/␤ heterodimers but had minimal activity on ER␣/␣ homodimers, posing a model that compounds promoting ER␣/␤ heterodimer formation might have therapeutic value. Thus, ER homodimer and heterodimer BRET assays are applicable to drug screening for dimer-selective selective ER modulators. Furthermore, this strategy can be used to study other nuclear receptor dimers. bioluminescence resonance energy transfer (BRET) ͉ estrogenic ligands ͉ selective estrogen receptor modulator (SERM) ͉ heterodimer ͉ homodimer T he biological actions of estrogens are mediated by estrogen receptors (ERs), which are ligand-inducible transcription factors. Binding of 17␤-estradiol (E 2 ) and other estrogenic compounds triggers receptor dimerization and subsequent association with estrogen response elements (EREs) in the promoter regions of ER-target genes to control gene transcription. ERs exist in two forms, ER␣ and ER␤, which have opposing roles in regulating estrogen action: ER␣ promotes whereas ER␤ inhibits estrogendependent cell growth (1, 2). It has been shown that the coexpression of ER␤ with ER␣ results in reduced ER␣-mediated proliferation of breast cancer cells. Approximately 60% of all breast tumors coexpress ER␣ and ER␤ (3, 4). Despite the findings that the coexpression of ER␤ has been correlated with a more favorable prognosis (5) and decreased biological aggressiveness compared with tumors expressing ER␣ alone (6, 7), whether ER␤ modulates ER␣ by heterodimerization to mediate growth-inhibitory phenotypes remains elusive. Multiple lines of evidence suggest that ER␣/␤ heterodimers do exist in vivo and may function to regulate distinct estrogen-responsive genes (8-10). However, the coexistence of homodimers has prevented a clear understanding of heterodimer function. Hypothetically, different estrogenic ligands could exert different cellular effects via differential induction of ER␣ homodimerization, ER␤ homodimerization, and ER␣/␤ heterodimerization. The differential regulation of these ER subtypes could be influenced by several factors including ligand-binding selectivity, conformational differences upon dimerization, d...

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Section: Discussionmentioning

confidence: 88%

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Powell

2008

Proc. Natl. Acad. Sci. U.S.A.

101

119

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“…However, in light of the most recent progresses in the area of the study of natural ligands for the ERs from nutritional sources, the term ''phytoestrogen'' appears to be inadequate or poorly representative of the actual activity of the lignans, when considering metabolic functions as functional targets. The reason is that it is becoming frequent to observe that the same molecules that bind and activate the ERs, also bind and activate other NRs that may play opposite actions on the regulation of target genes (i.e., PPARc) and activate NR cross-talks with outcomes that are not clear [31,56,57]. An example of a lignan that binds the PPARs is macelignan [58,59], which has been determined as a dual ligand for PPARa/c receptors.…”

Section: Discussionmentioning

confidence: 99%

Oilseeds ameliorate metabolic parameters in male mice, while contained lignans inhibit 3T3-L1 adipocyte differentiation in vitro

et al. 2014

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Purpose and background The focus was directed to the study of two of the most lignan-rich food sources: sesame and flaxseeds. Recent epidemiological and experimental evidences suggesting that these foods may improve metabolic functions underlying metabolic syndrome (MetS). Methods To characterize the effect of these oilseeds on metabolic functions, we conducted an experimental study aimed at preventing adiposity and metabolic imbalance in a mouse model of high-fat diet (HFD)-induced MetS. Statistical analysis was performed by two-way analysis of variance test followed by post hoc Bonferroni analysis. Results We studied the effect of the oilseeds sesame and flaxseed on metabolic parameters in mice on a HFD. When the HFD was integrated with 20 % of sesame or flaxseed flours, the mice showed a decrease in body fat, already at day 15, from time 0. The size of the adipocytes was smaller in epididymal fat, liver steatosis was inhibited, and insulin sensitivity was higher in mice on the supplemented diets. The supplemented diets also resulted in a significant increase in the serum levels of the lignan metabolites enterodiol and enterolactone compared with the controls. The expression of genes associated with the inflammatory response, glucose metabolism, adipose metabolism and nuclear receptor were altered by the oilseed-supplemented diets. Some of the most abundant lignans in these oilseeds were studied in 3T3-L1 preadipocyte cells and were effective in inhibiting adipocyte differentiation at the minimal dose of 1 nM. Conclusions The consumption of sesame and flaxseed may be beneficial to decrease metabolic parameters that are generally altered in MetS.

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“…The latter step resulted in the removal of endogenous oestrogens from the extract. The extract was reconstituted in dimethyl sulfoxide (DMSO) to make it water soluble before tested in an oestrogen-receptor transactivation assay with T47D.luc cells (Dip et al, 2008).…”

Section: Sample Preparation For Test Of Milk Bioactivesmentioning

confidence: 99%

Cell-based models to test the effects of milk-derived bioactives

Purup

Nielsen²

2012

Animal

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The life science industries have a strong interest in screening for novel bioactives in complex mixtures like milk and dairy products. Food bioactives are not only important for public health in general, but also have potential therapeutic applications for the treatment of a number of diseases. To identify these novel bioactives, establishment of robust screening assays is essential. The use of in vitro cell-based models for screening and testing have the advantage that several concentrations of mixtures or specific compounds can be assayed at the same time in cells from specific tissues. Primary cell cultures from target organs or established cell lines can be used to identify the most sensitive cells. In addition, a large number of transfected cell lines with very specific sensitivities have been developed. Different endpoints inherent to basal or more sophisticated cellular functions can be investigated, such as cell viability, apoptosis, migration, intracellular signalling, regulation of gene expression, morphology and metabolic alterations. The gastrointestinal tract is an obvious target for bioactive molecules delivered through milk and dairy products, because it lies at the interface between dietary components in the lumen and the internal processes of the host. Identification of bioactive factors that affects proliferation or migration of epithelial cells may have potential applications in promoting gastrointestinal health in both humans and animals. The mammary gland is another target organ of considerable interest since it has been estimated that up to 50% of all newly diagnosed breast cancers may be related to dietary factors. A large number of gastrointestinal and mammary epithelial cell lines are commercially available, but in order to study some cellular functions, primary cultures of freshly isolated cells are often preferred, as established cell lines do not always express specialised properties in culture.

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Global gene expression profiles induced by phytoestrogens in human breast cancer cells

Cited by 49 publications

References 55 publications

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Oilseeds ameliorate metabolic parameters in male mice, while contained lignans inhibit 3T3-L1 adipocyte differentiation in vitro

Cell-based models to test the effects of milk-derived bioactives

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