stilbenes and Endometrial-Neoplasms

The recognition of selective estrogen receptor modulation in the laboratory has resulted in the development of two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, for clinical application in healthy women. SERMs are antiestrogenic in the breast but estrogen-like in the bones and reduce circulating cholesterol levels. SERMs also have different degrees of estrogenicity in the uterus. Tamoxifen is used specifically to reduce the incidence of breast cancer in premenopausal and postmenopausal women at risk for the disease. In contrast, raloxifene is used specifically to reduce the risk of osteoporosis in postmenopausal women at high risk for osteoporosis. The study of tamoxifen and raloxifene (STAR) trial is currently comparing the ability of these SERMs to reduce breast cancer incidence in high-risk postmenopausal women. There is intense interest in understanding the molecular mechanism(s) of action of SERMs at target sites in a woman's body. An understanding of the targeted actions of this novel drug group will potentially result in the introduction of new multifunctional medicines with applications as preventive agents or treatments of breast cancer and endometrial cancer, coronary heart disease, and osteoporosis.

Topics: Adult; Aged; Bone and Bones; Breast; Breast Neoplasms; Cardiovascular System; Cinnamates; Clinical Trials as Topic; Coronary Disease; Endometrial Neoplasms; Estrogen Replacement Therapy; Female; Heart; Hot Flashes; Humans; Middle Aged; Models, Biological; Organ Specificity; Osteoporosis; Postmenopause; Premenopause; Prospective Studies; Protein Structure, Tertiary; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Receptors, Estrogen; Risk; Risk Assessment; Selective Estrogen Receptor Modulators; Stilbenes; Tamoxifen; Thrombophilia; Transcription, Genetic

Resveratrol has long been known as an antioxidant and a chemopreventive agent. Similar to resveratrol, pterostilbene (PT) is also a phenolic compound extracted from the Vitis species. However, there are few studies on the antitumor effect of PT. Thus, we investigated the effects of PT on the endometrial cancer (EC) cells in vitro and the related molecular mechanisms. Treatment of EC cell lines HTB-111 and Ishikawa with PT (25-100 μmol/L) dose-dependently suppressed the cell viability and induced apoptosis. Using miR microarrays, we examined the miR expression profile in Ishikawa cells with or without PT, and revealed that miR-663b was the most decreased in PT-treated Ishikawa cells. Furthermore, we predicted and verified that the pro-apoptosis factor BCL2L14 is the direct target of miR-663b. Over-expression of miR-663b and knock-down of BCL2L14 counteracted the suppressing effects of PT on HTB-111 and Ishikawa cells. In addition, we evaluated the miR-663b levels in EC tissues of 51 patients using an in situ hybridization technique. With the median of the score of miR-663b as a cut-off value, these EC patients were divided into two groups, and the patients with high miR-663b expression had significantly poor prognosis.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Endometrial Neoplasms; Female; Gene Knockdown Techniques; Humans; MicroRNAs; Prognosis; Proto-Oncogene Proteins c-bcl-2; Stilbenes; Vitis

Endometrial cancer is the most common gynecologic cancer in the United States and its incidence and mortality has been rising over the past decade. Few treatment options are available for patients with advanced and recurring endometrial cancers. Novel therapies, which are frequently toxic, are difficult to establish in this patient population which tends to be older and plagued by comorbidities such as diabetes mellitus and hypertension. Therefore, novel, non-toxic therapies are urgently needed. Megestrol acetate is a frequently used drug in endometrial cancer patients. However, its response rate is only 20-30%. To enhance the activity of megestrol acetate in endometrial cancer patients, we explored the potential of combining natural supplements with megestrol acetate and found that the addition of the natural phenolic compound, pterostilbene, to megestrol acetate resulted in a synergistic inhibition of cancer cell growth in vitro and an enhanced reduction of tumor growth in a xenograft mouse model. In addition, dual treatment led to attenuation of signaling pathways, as well as cell cycle and survival pathways. Our results demonstrated for the first time that the anti-tumor activity of megestrol acetate can be enhanced by combining with pterostilbene, providing an insight into the potential application of pterostilbene and megestrol acetate combination for the treatment of endometrial cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Endometrial Neoplasms; Female; Humans; MAP Kinase Signaling System; Megestrol Acetate; Mice, Nude; Phenols; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Xenograft Model Antitumor Assays

Endometrial cancer, in developed countries, is the most common malignancy of the female genital tract. Surgery and radiotherapy are successful in many patients but systemic and recurrent diseases have no consistently effective treatments, and for high grade advanced disease the prognosis is poor. The study investigated characteristics of adrenomedullin in endometrial cancer to assist in identifying targets for developing treatments.. Endometrial samples of women with and without cancer, and the Ishikawa cell line were used to investigate adrenomedullin mRNA regulation, peptide expression, adrenomedullin secretion and effects of adrenomedullin on VEGF secretion.. Expression of adrenomedullin mRNA was upregulated compared to that in healthy post-menopausal endometria. Adrenomedullin secretion was increased by cobalt chloride in this study. Secretion was reduced by the naturally-occurring compounds, (-)-epigallocatechin gallate (EGCG) and 3,4',5-trihydroxystilbene (resveratrol), which we have previously demonstrated to also suppress VEGF secretion in endometrial tumour tissue. We noted, for the first time, that adrenomedullin enhanced VEGF secretion from tumour cells.. Increased adrenomedullin expression may result in amplifying both tumorigenic and angiogenic activities. A substantial impact on growth of tumours may result in vivo as a consequence of the synergism between adrenomedullin and VEGF. Adrenomedullin, which has altered cellular characteristics in tumour compared to healthy tissue, offers an understudied target with potential to modify endometrial cancer behaviour, complementing other treatments.

Topics: Adenocarcinoma; Adrenomedullin; Biomarkers, Tumor; Case-Control Studies; Catechin; Cell Line, Tumor; Cobalt; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Grading; Resveratrol; RNA, Messenger; Stilbenes; Up-Regulation; Vascular Endothelial Growth Factor A

Resveratrol is emerging as a novel anticancer agent. However, the mechanism(s) by which resveratrol exerts its effects on endometrial cancer (EC) are unknown. We previously reported that beta-arrestin 2 plays a critical role in cell apoptosis. The role of ß-arrestin 2 in resveratrol modulation of endometrial cancer cell apoptosis remains to be established.. EC cells HEC1B and Ishikawa were transfected with either ß-arrestin 2 RNA interfering (RNAi) plasmid or beta-arrestin 2 full-length plasmid and control vector. The cells were then exposed to differing concentrations of resveratrol. Apoptotic cells were detected by TUNEL assay. Expression of total and phosphorylated Akt (p-Akt), total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3ß), and caspase-3 were determined by Western blot analysis. Our data demonstrate that inhibition of ß-arrestin 2 increases the number of apoptotic cells and caspase-3 activation. Additionally ß-arrestin 2 exerted an additive effect on resveratrol-reduced levels of p-Akt and p-GSK3ß. Overexpression of ß-arrestin 2 decreased the percentage of apoptosis and caspase-3 activation and attenuated resveratrol-reduced levels of p-Akt and p-GSK3ß. Taken together, our studies demonstrate for the first time that ß-arrestin 2 mediated signaling plays a critical role in resveratrol-induced apoptosis in EC cells.. Resveratrol primes EC cells to undergo apoptosis by modulating beta-arrestin 2 mediated Akt/GSK3ß signaling pathways.. These inspiring findings would provide a new molecular basis for further understanding of cell apoptotic mechanisms mediated by ß-arrestin 2 and may provide insights into a potential clinical relevance in EC.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Arrestins; beta-Arrestin 2; beta-Arrestins; Caspase 3; Cell Line, Tumor; Endometrial Neoplasms; Enzyme Activation; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; RNA Interference; Signal Transduction; Stilbenes

A series of structurally simple bibenzyl-diol and stilbene-diol core molecules, structural analogs of the well-known hexestrol and diethylstilbestrol non-steroidal estrogens, were prepared and evaluated as estrogen receptor (ER) subtype-selective ligands. Analysis of their ERalpha and ERbeta binding showed that certain substitution patterns engendered binding affinities that were >100-fold selective for ERbeta. When further investigated in cell-based gene transcription assays, some molecules showed similarly high relative transcriptional potency selectivity in favor of ERbeta. Interestingly, the most ERbeta-selective molecules were those bearing non-polar substituents on one of the internal carbon atoms. These compounds should be useful probes for determining the physiological roles of ERbeta, and they might lead to the development of more selective and thus safer pharmaceuticals.

Topics: Bibenzyls; Cell Line, Tumor; Endometrial Neoplasms; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Ligands; Protein Binding; Stilbenes; Transcription, Genetic

Our purpose was to establish whether resveratrol and (-)-epigallocatechin-3-gallate (EGCG), two compounds extracted from food, would reduce the amount of Vascular Endothelial Growth Factor (VEGF) secreted into the supernatants of cultured endometrial cancer cells.. Endometrial cancer samples were collected from 19 consenting women who were undergoing hysterectomy operations to remove tumours. Tumour cells were dispersed into single cell suspensions and cultured. Two immortalised cell lines were also studied. After incubating cells under various test and control conditions, ELISA was used to measure VEGF levels in the supernatants.. VEGF was measurable at varied concentrations in the supernatants of cultured cells, from both cell lines and primary cultures. Cobalt chloride (CoCl(2)), a hypoxia mimic, increased the measured secretion of VEGF from these cells. In contrast, treatment with either resveratrol or EGCG significantly reduced secretion of VEGF. Further, resveratrol and EGCG inhibited release from cells that were also exposed to CoCl(2).. Both resveratrol and EGCG induced significant reductions in the amount of VEGF secreted into the supernatant of cultured endometrial cancer cells. These results suggest that resveratrol and EGCG may have the potential to inhibit angiogenesis in endometrial tumours. Further investigation of these substances in endometrial cancer is warranted.

Topics: Anticarcinogenic Agents; Catechin; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Humans; Resveratrol; Stilbenes; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Several anthropogenous and naturally occurring substances, referred to as estrogen active compounds (EACs), are able to interfere with hormone and in particular estrogen receptor signaling. EACs can either cause adverse health effects in humans and wildlife populations or have beneficial effects on estrogen-dependent diseases. The aim of this study was to examine global gene expression profiles in estrogen receptor (ER)-proficient Ishikawa plus and ER-deficient Ishikawa minus endometrial cancer cells treated with selected well-known EACs (diethylstilbestrol, genistein, zearalenone, resveratrol, bisphenol A and o,p'-DDT). We also investigated the effect of the pure antiestrogen ICI 182,780 (ICI) on the expression patterns caused by these compounds. Transcript levels were quantified 24 h after compound treatment using Illumina BeadChip Arrays. We identified 87 genes with similar expression changes in response to all EAC treatments in Ishikawa plus. ICI lowered the magnitude or reversed the expression of these genes, indicating ER dependent regulation. Apart from estrogenic gene regulation, bisphenol A, o,p'-DDT, zearalenone, genistein and resveratrol displayed similarities to ICI in their expression patterns, suggesting mixed estrogenic/antiestrogenic properties. In particular, the predominant antiestrogenic expression response of resveratrol could be clearly distinguished from the other test compounds, indicating a distinct mechanism of action. Divergent gene expression patterns of the phytoestrogens, as well as weaker estrogenic gene expression regulation determined for the anthropogenous chemicals bisphenol A and o,p'-DDT, warrants a careful assessment of potential detrimental and/or beneficial effects of EACs. The characteristic expression fingerprints and the identified subset of putative marker genes can be used for screening chemicals with an unknown mode of action and for predicting their potential to exert endocrine disrupting effects.

Topics: Benzhydryl Compounds; Cell Line, Tumor; Cluster Analysis; DDT; Diethylstilbestrol; Endocrine Disruptors; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Estrogens; Female; Fulvestrant; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genistein; Humans; Oligonucleotide Array Sequence Analysis; Phenols; Phytoestrogens; Polymerase Chain Reaction; Receptors, Estrogen; Reproducibility of Results; Resveratrol; Risk Assessment; RNA, Messenger; Stilbenes; Time Factors; Zearalenone

Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. Resveratrol, a natural anti-oxidant found in red wine emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on uterine cancer cells is poorly understood. At the molecular level, resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. The aim of the present study was to determine if resveratrol could exert anti-proliferative and pro-apoptotic activity over uterine cancer cells upon inhibition of COX-2 expression and/or activity. Six different human uterine cancer cell lines were used as a model (HeLa, Hec-1A, KLE, RL95-2, Ishikawa and EN-1078D).. High-dose of resveratrol triggered apoptosis in five out of six uterine cancer cell lines, as judged from Hoechst nuclear staining and effector caspase cleavage. In accordance, uterine cancer cell proliferation was decreased. Resveratrol also reduced cellular levels of the phosphorylated/active form of anti-apoptotic kinase AKT. Endogenous COX-2 protein levels were decreased, concomitant with a decrease in production of COX metabolites PGE2 and PGF2alpha, in each uterine cancer cell line expressing detectable levels of COX-1 and/or COX-2 in presence of resveratrol. Although COX expression was identified as a target of resveratrol in uterine cancer cells, inhibition of COX activity or exogenously added PGE2 did not modulate the effect of resveratrol on cellular proliferation.. High-dose of resveratrol exerts tumoricidal activity over uterine cancer cells and regulates COX expression. In these cells, resveratrol would not directly target COX activity, but possibly other enzymes involved in prostaglandin synthesis that act downstream of the COXs.

Topics: Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endometrial Neoplasms; Female; HeLa Cells; Humans; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Uterine Neoplasms

Resveratrol and other polyphenols have anti-carcinogenic and anti-tumorigenic activities in various carcinomas. However, such studies are limited in endometrial cancer. We hypothesize that resveratrol suppresses cancer growth through modulation of cell cycle and cell growth regulatory genes. To test this hypothesis, we treated endometrial cancer cells (Ishikawa cell line) with resveratrol (1, 10, 50 and 100 micro M) for 1, 3, 5 and 7 days, and analyzed for growth signal genes (EGF and VEGF), cell cycle regulatory genes (p53 and p21), and apoptosis-related genes (bcl-2 and bax). Results of these experiments demonstrate that after resveratrol treatment, the growth of Ishikawa cells was inhibited in a dose dependent manner. The gene and protein expression data suggest that resveratrol treatment significantly decreased EGF, whereas VEGF was up-regulated in Ishiwaka cell lines. Interestingly, protein expressions of p21 and Bax were decreased, even though their mRNA expressions did not show significant changes. The present study suggests that resveratrol can suppress proliferation of Ishikawa cells through down-regulation of EGF.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Cell Cycle; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Endometrial Neoplasms; Epidermal Growth Factor; Female; Humans; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Time Factors

Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth.. Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naïve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands.. Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naïve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naïve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice.. GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naïve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.

Topics: Animals; Cinnamates; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Transplantation; Raloxifene Hydrochloride; Receptors, Estrogen; Stilbenes; Tamoxifen; Transplantation, Heterologous; Tumor Cells, Cultured

Tamoxifen is the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer, and it is the first drug approved to reduce the incidence of breast cancer in high-risk women. Unfortunately, tamoxifen also possesses some estrogen-like effects in the uterus that cause a modest increase in the risk of endometrial cancer. GW5638 is a tamoxifen derivative with a novel carboxylic acid side chain with no uterotropic activity in the rat (Willson et al., J Med Chem, 1994, 37:1550-1552). We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10(-11)-10(-6) M), but 4-OHT was weakly estrogen-like at low concentrations (10(-11)-10(-10) M). Compounds (10(-7) M) blocked the growth promoting action of estradiol (10(-10) M) in both ECC-1 and MCF-7 cells. Western blotting was used to show that GW7604 and raloxifene did not affect ER levels significantly, compared with controls, in MCF-7 cells; whereas the pure antiestrogen ICI182,780 decreased ER levels (P < 0.05). An assay system was used that can classify compounds into tamoxifen-like, raloxifene-like, or pure antiestrogens. The assay depends on the activation of the transforming growth factor alpha (TGFalpha) gene in situ by wild-type or D351Y mutant ER stably transfected into MDA-MB-231 cells (MacGregor-Schafer et al., Cancer Res, 1999, 59:4308-4313). GW7604 inhibited both estradiol (10(-9) M) and 4-OHT (10(-8), 10(-7) M) induction of TGFalpha in a concentration related manner (10(-9)-10(-6) M). GW7604 and raloxifene stimulated TGFalpha with the D351Y ER. In contrast, ICI 182,780 (10(-6) M) did not initiate TGFalpha and blocked the induction of TGFalpha with GW7604, raloxifene, and 4-OHT in D351Y-transfected cells. Using computer-assisted molecular models of ER complexes, we found that the antiestrogenic side chain of 4-OHT weakly interacted with the surface amino acid 351 (aspartate), but the carboxylic acid of GW7604 caused a strong repulsion of aspartate 351. We propose that GW7604 is less estrogen-like than 4-OHT, because it disrupts the surface charge around aa351 required for coactivator docking in the 4-OHT:ER complex. This charge is restored in the D351Y ER, thus converting GW7604 from an antiestrogen to an estrogen-like molecule.

Topics: Carcinoma; Cell Division; Cinnamates; Endometrial Neoplasms; Estrogen Receptor alpha; Estrogen Receptor Modulators; Estrogens; Female; Gene Expression Regulation; Humans; Models, Molecular; Receptors, Estrogen; RNA, Messenger; Selective Estrogen Receptor Modulators; Stilbenes; Tamoxifen; Transforming Growth Factor alpha; Tumor Cells, Cultured

Trans-3,4',5-trihydroxystilbene (resveratrol), a polyphenolic compound found in the human diet, was reported recently to serve as an estrogen agonist with cultured MCF-7 cells transfected with estrogen response element-luciferase reporter plasmids. As currently shown, treatment of cultured human endometrial adenocarcinoma (Ishikawa) cells with resveratrol (concentrations as high as 10 microM) did not significantly increase the levels of an estrogen-inducible marker enzyme, alkaline phosphatase. To the contrary, when alkaline phosphatase was induced by treatment with 1 nM of 17beta-estradiol (E(2)), resveratrol exhibited a dose-dependent decrease in activity (IC(50) = 2.3 microM). Furthermore, when Ishikawa cells were treated with resveratrol as a single agent, estrogen-inducible progesterone receptor (PR) was not enhanced, and PR expression induced by treatment with E(2) was inhibited by resveratrol in a dose-dependent fashion at both the mRNA and protein levels. In addition, resveratrol mediated suppression of a functional activity of PR as demonstrated by down-regulation of alpha(1)-integrin expression induced by E(2) plus progesterone. With transient transfection experiments conducted with Ishikawa cells, antiestrogenic effects were confirmed by dose-dependent inhibition of E(2)-induced estrogen response element-luciferase transcriptional activity. Because resveratrol antagonized estrogenic effects in Ishikawa cells, competitive binding analyses were performed to examine the potential of displacing [(3)H]E(2) from human estrogen receptor (ER). Resveratrol showed no discernable activity with ER-alpha, but with ER-beta, E(2) was displaced with an IC(50) of 125 microM. However, mRNA and protein expression of ER-alpha but not ER-beta were suppressed by resveratrol in Ishikawa cells, in the concentration range of 5-15 microM. In addition, in the presence or absence of E(2), resveratrol inhibited Ishikawa cell proliferation in a time-dependent manner with cells accumulating in the S phase of the cycle < or =48 h. This effect was reversible. Analysis of some critical cell cycle proteins revealed a specific increase in expression of cyclins A and E but a decrease in cyclin-dependent kinase 2. These data suggest resveratrol exerts an antiproliferative effect in Ishikawa cells, and the effect may be mediated by both estrogen-dependent and -independent mechanisms.

Topics: Adenocarcinoma; Alkaline Phosphatase; Antigens, CD; Antineoplastic Agents, Phytogenic; CDC2-CDC28 Kinases; Cell Survival; Cyclin A; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Down-Regulation; Drug Interactions; Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptor Modulators; Female; Gene Expression Regulation, Neoplastic; Humans; Integrin alpha1; Protein Serine-Threonine Kinases; Receptors, Estrogen; Receptors, Progesterone; Resveratrol; RNA, Messenger; S Phase; Stilbenes; Transcriptional Activation; Tumor Cells, Cultured