Estrogen Alpha Research Articles

Clinical implications of ERβ methylation on sporadic breast cancers in Chinese women

Estrogens play a key role in the genesis and progression of breast cancer, activating two estrogen receptors, alpha and beta (ERα and ERβ). We have previously observed that ERα methylation occurs in high frequency and may be one of the mechanisms of ERα expression silence in a subset of Chinese sporadic breast cancers. However, the ERβ promoter methylation status and the relationship between clinicopathological characteristics and ERβ methylation in sporadic breast cancer are still unknown, especially in Chinese women. This study acted to determine the methylation status of the ERβ promoter and its correlation with clinicopathological features of sporadic breast cancers in Chinese women, and lay a foundation for the management of breast cancer. In total, 178 cases with sporadic breast cancers were enrolled in the study. ERβ methylation was determined using a methylation-specific polymerase chain reaction (MSP). In general, ERβ promoter methylation was found in 44.9% (80/178) of breast tumor samples, significantly higher than the benign breast hyperplasia (44.9% vs. 14.3%, X(2) = 4.986, P = 0.026). A total of 58% (40/69) of ERβ-negative tumors got methylation compared with 36.7% (40/109) of ERβ-positive cases being methylated (X(2) = 7.728, P = 0.005). The levels of ERβ protein expression diminished with the frequency of ERβ methylation (r = -0.249, P < 0.0001). In addition, we observed a strong correlation between ERα promoter and ERβ promoter methylation (odds ratio 2.054, 95% confidence interval 1.086-3.886, P = 0.026), and the triple-negative tumors showed a significantly higher methylation rate of ERβ. This study presents, for what we believe to be the first time, that ERβ methylation is also a frequent event in breast cancer and maybe also one of the mechanisms of ERβ expression silence in a subset of Chinese sporadic breast cancers. Epigenetic alteration of the ERβ gene may play an important role in the pathogenesis of breast cancer.

Protection by Red Wine Polyphenols against Metabolic and Cardiovascular Alterations Associated with Obesity: A Possible Link with Estrogen Alpha Receptor

Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular and metabolic diseases. Red wine contains a wide variety of polyphenols (RWPC), which mainly derive from grape solids (skin and seeds) and can be divided into two classes, flavonoids and non-flavonoids. RWPC exert numerous effects including antioxidant and free radical properties, anti-platelet aggregating and anti-thrombotic activities. Moreover, RWPC are powerful vasodilators and contribute to the preservation of the integrity of the endothelium and to the inhibition of smooth muscle cell proliferation and migration. All these effects of red wine may interfere with atherosclerotic plaque development and stability, vascular thrombosis and occlusion and explain the prevention of ischemic heart disease, stroke and metabolic diseases observed in different experimental models. With regard to obesity, we studied the effects of dietary supplementation of RWPC in Zucker fatty rats (ZF). We show that RWPC lead to an improvement of glucose and lipid metabolism in ZF rats, enhances cardiac function and decreases peripheral resistance. In addition, RWPC improve endothelium-dependent relaxation in both aorta and small mesenteric arteries from ZF rats, an effect accompanied by an increase of vascular nitric oxide (NO) production and a decrease of superoxide anions release, resulting in an increase of NO bioavailability. Thus, RWPC lead to an overall improvement in obesity-associated alterations, including glucose and lipid metabolism, as well as endothelial and cardiac functions. A molecular basis of the effect of RWPC has been provided on the endothelium, indentifying the alpha isoform of the estrogen receptor (ERα) as the key receptor, or at least one of those transducing vascular effects exerted by these compounds, particularly delphinidin with respect to NO production. These results are of importance inasmuch as RWPC, by interacting with ERα, can activate other targets such the sirtuin-1-adenosine monophosphate protein kinase network, both of which are amongst the most potent regulators of cellular metabolism, including vascular cells, adipocytes and hepatocytes. Altogether, the available evidence indicates that RWPC might be of therapeutic benefit for cardiovascular and metabolic protections, although prospective controlled clinical trials are still needed.

Sex hormones receptors play a crucial role in the control of femoral and mandibular growth in newborn mice

Sex hormones are important for bone growth. However, the mechanism by which sex hormone receptors influence bone growth remains unclear. In orthodontic treatment, there is a need to develop an indicator of bone maturity to accurately predict the beginning and end of growth. This indicator might be developed from the screening of sex hormones. The purpose of this study was to investigate the role of each sex hormone receptor on bone growth in newborn mice. Five-day-old C57BL/6J mice were used in this experiment. Forty mice underwent an orchiectomy (ORX), ovariectomy (OVX), or sham surgery. One week after surgery, the femur and the mandible were resected for immunohistochemical staining. Alternatively, 80 mice were daily injected with antagonist against receptors oestrogen alpha (ERα), beta (ERβ), or androgen receptor (AR). One week after the first injection, radiographs of the femur and mandible were taken and then measured. Analysis of variance and pairwise comparisons (Fisher) were performed to examine the differences in values measured among the groups In the sham-operated male and female mice, ERβ was found to be more prominent than ERα and AR during all experimental periods. In the ORX and OVX groups, the expressions of all receptors were significantly reduced in comparison with the sham-operated control group throughout the experiment. Moreover, femur and mandibular growth were significantly affected in the group injected with ERβ antagonist. The deficiency of any sex hormone leads to reduced bone growth. In particular, a disturbance in ERβ produces a greater aberrance in both male and female mice immediately after birth.

MTD-PLS and docking study for a series of substituted 2-phenylindole derivatives with oestrogenic activity

AbstractA series of 36 substituted 2-phenylindoles was analysed using minimal topological difference-projections in latent structures variant (MTD-PLS) and molecular docking, using fast rigid exhaustive docking (FRED) and AutoDock Vina programs. For quantitative structure activity relationships (QSAR) validation, a sphere exclusion algorithm in the multi-dimensional descriptor space was used to construct training and test sets. Docking procedures were based on X-ray crystallography studies using the human alpha oestrogen receptor-17β-oestradiol complex. The ranking abilities of the different scoring functions of the FRED package were presented, and the most suitable scoring function (Chemgauss3) for the oestrogen receptor was chosen. Although the series studied contains only a limited number of compounds, the MTD-PLS method and the docking procedure provided coherent results in concordance with the X-ray diffraction data for different ligand-oestrogen receptor complexes.

17Beta-estradiol attenuates programmed cell death in cortical pericontusional zone following traumatic brain injury via upregulation of ERalpha and inhibition of caspase-3 activation

Pericontusional zone (PCZ) of traumatic cerebral contusion is a target of pharmacological intervention. It is well studied that 17beta-estradiol has a protective role in ischemic brain injury, but its role in brain protection of traumatic brain damage deserves further investigation, especially in pericontusional zone. Here we show that 17beta-estradiol enhances the protein expression and mRNA induction of estrogen alpha receptor (ERalpha) and prevents from programmed cell death in cortical pericontusional zone. ERalpha specific antagonist blocks this protective effect of 17beta-estradiol. Caspase-3 activation occurs in cortical pericontusional zone of the oil-treated injured rat brain and its activation is inhibited by 17beta-estradiol treatment. Additionally, ERalpha specific antagonist reverses this inhibition. Pan-caspase inhibitor also protect cortical pericontusional zone from programmed cell death. Our present study indicates 17beta-estradiol protects from programmed cell death in cortical pericontusional zone via enhancement of ERalpha and decrease of caspase-3 activation.

Immunohistochemical Localization of Estrogen Alpha and Beta Receptors and Aromatase Cytochrome P450 in Adult Stallion Testicles.

Immunohistochemical Localization of Estrogen Alpha and Beta Receptors and Aromatase Cytochrome P450 in Adult Stallion Testicles.

The effects of tooth movement on estrous-cycle-dependent expression of the estrogen receptor α

The aim of this study was to explore the effects of applying force during the different stages of the estrous cycle on the dynamic expression of alpha estrogen receptors (ERα) and the rate of tooth movement, to provide insight into the timing of effective treatment. A repeated, intermittent force was loaded on the first upper molar of female rats five times during specific stages of the estrous cycle. The distance of tooth movement was measured. ERα protein and mRNA levels in the periodontal tissue were measured, and the data were analyzed by ANOVA, Student–Newman–Keuls (SNK) and cosinor analysis. The results showed that ERα expression varied among the subgroups that received force during different stages of the estrous cycle and exhibited an infradian rhythm in both groups. There were significant variations in the amount of tooth movement among the four subgroups (P < 0.01). We conclude that the highest ERα expression and the fastest periodontal remodeling were in the rats that received force during estrus.

Paravertebral deep back muscles of girls with idiopathic scoliosis reveal expression of receptors for estrogens

Estrogens can influence skeletal muscles activity by stimulating angio- and muscle-genesis. These hormones act through specific alpha and beta estrogen receptors (ER). Muscular tissue may be a target for estrogens, however there is no data on ER expression in paravertebral muscles in patients with idiopathic scoliosis (IS). During early adolescence the increase of estrogen serum level coincidences with the period of rapid scoliosis progression. The aim of the study was to investigate ER alpha expression in the paravertebral muscles of patients with IS.

Expression of estrogen alpha and beta receptors in prostate cancer and hyperplasia: Immunohistochemical analysis

Estrogen receptors are believed to play a significant role in the pathogenesis of prostate carcinoma (PCa). The aim of this study is to evaluate the expression of ER-α and ER-β in human benign and malignant prostatic tissue. The archival materials of 100 prostatic specimens (65 PCa, 35 BPH) were collected from the Department of Pathology, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia. Seven PCa cases contained foci of high-grade prostate intraepithelial neoplasia (HGPIN). Immunohistochemistry was used to test the protein expression of ER-α and ER-β utilizing monoclonal mouse antihuman antibodies. Among the 65 cases of PCa, ER-α was expressed in 3 cases (4.6%) in epithelial cells and 4 cases (6.1%) in stromal cells. ER-α was not expressed in any of the HGPIN foci. Additionally, ER-α was not expressed in either luminal or basal cells in any of the 35 BPH cases. However it was expressed in 4 cases (11.4%) in stromal cells of BPH. In PCa, ER-β was expressed in 61 cases (93.8%) and 35 cases (53.8%) in the epithelial and stromal cells respectively. ER-β was expressed only in 2 cases (28.5%) out of 7 HGPIN foci. It was expressed in 33 cases (94.3%) of epithelial and stromal cells of BPH. The majority of PCa and BPH exhibited nuclear immunoreactivity for ER-β in both tumor and stromal cells and they are usually negative for ER-α. There is probably partial loss of ER-β in HGPIN. ER-β may have a role in the process of prostatic hyperplasia and malignancy.

Estrogen Receptor 1 Gene (ESR1) is Associated with Restrictive Anorexia Nervosa

Anorexia nervosa (AN) is a highly heritable young-onset psychiatric illness the etiology of which remains unknown. Estrogen alpha and beta receptors, encoded by ESR1 and ESR2 genes, are involved in food intake regulation and eating behavior, and may have a potential role in AN. We performed a family-based association study of 17 single-nucleotide polymorphisms (SNPs) encompassing ESR1 and ESR2 genes in a cohort of 321 French AN families. We attempted to replicate this finding in a cohort of 41 restrictive AN (RAN) families and in a population-based study of 693 young women. Using the transmission disequilibrium test, a significant over-transmission was detected between AN and ESR1 rs726281 and rs2295193. These SNPs and another among ESR1 were more specifically associated with the RAN subtype (rs726281, p=0.005, odds ratio (OR)=2.1, 95% confidence interval (95% CI)=1.2-3.6; rs3798577, p=0.021, OR=1.6, 95% CI=1.1-2.3; and rs2295193, p=0.007, OR=1.7, 95% CI=1.2-2.5). A large eight-SNPs haplotype of ESR1 gene was also associated with AN (p<0.0001, OR=3.1, 95% CI=1.8-5.1). Association of ESR1 SNPs and RAN was driven by paternal over-transmissions (p<0.0001, OR=3.7, 95% CI=1.9-7.3). Furthermore, we confirmed the preferential paternal over-transmission of the ESR1 rs726281 on the independent German sample of 41 RAN trios (p=0.025, OR=3, 95% CI=1.1-8.3). Finally, rs3798577 was associated with eating disorders in a population-based sample of 693 women (p<0.01). Our findings are strongly in favor of an association between ESR1 polymorphisms and AN. In particular, ESR1 gene confers a high risk of vulnerability to the restrictive subtype of AN, and suggests that the estrogen pathway has to be further analyzed in AN.

Estrogen receptor beta participate in the regulation of metabolizm of extracellular matrix in estrogen alpha negative breast cancer.

The biology of breast cancer is closely releted to sex steroid hormones. Estrogen receptor beta is overexpressed in around 70% breast cancer cases, referrd to as "ER positive". Estrogens bind to estrogen receptor and stimulate the transcription of genes involved in control of cell proliferation. Moreover, estrogens may induce growth factors and components of extracellular matrix and interact with them in a complex manner. Extracellular matrix and integrins play an important role in cell functions and their aberrant expressions are implicated in breast cancer development, invasion and metastasis. ER beta is certainly associated with more differentiated tumors, while evidence of role of ER beta is controversial. The highly invasive breast cancer ER beta negative cell line MDA-MB 231 can be the model of exam the role of ER beta in breast cancer. The aim of this study was to examine the role of activation of ER beta on the metabolism of the extracellular matrix and the expression of beta-1 integrin in the breast cancer cell line MDA-MB 231. The cells were exposed on the estradiol, tamoxifen, raloxifen and genisteina in dose dependent concentrations. To determine the relative rate of collagen syntesis we measured the time-dependent reduction of collagen-bound radioactivity after pulse-chase labeling with [3 H] prolina by Peterkofsky methods. The expression of beta-1 integrin was determine by Western blot analysis. The activity of MMP2 and 9 were measured using gelatin zymography with an image analysis system. Our data suggest on the role of estrogen receptor beta on the metabolism of extracellular matrix in the breast cancer line MDA - MB 231. Estradiol and SERMs regulate the expression of ECM proteins: collagen, integrins and enhance activity of metaloproteinases 2 and 9.

Endothelium-independent vasorelaxation by the selective alpha estrogen receptor agonist propyl pyrazole triol in rat aortic smooth muscle

Abstract Objectives This study investigated the signalling mechanism of the relaxant responses to the estrogen receptor alpha (ERα) agonist PPT (propyl pyrazole triol) in endothelium-denuded rat aortic rings. Methods Several compounds, including protein kinase G (PKG) inhibitors and potassium channel inhibitors, were tested against PPT-dependent rat aortic relaxation. Cyclic GMP and cytosolic calcium responses to PPT in isolated aortic smooth muscle were investigated in parallel. Key findings PPT vasorelaxation was largely reduced by the selective ERα antagonist methyl-piperidinopyrazole (MPP; −91.6 ± 2.5%), by the selective PKG inhibitor Rp-8-Br-cGMP (−78.6 ± 4.9%), by the specific soluble guanylyl cyclase inhibitor ODQ (1H-(1,2,4)-oxadiazolo[4,3-a]quinoxalin-1-one; −85.3 ± 5.2%) and to a lesser extent by the selective BKCa (large-conductance calcium- and voltage-activated potassium channel) inhibitor iberiotoxin (−59.3%), the selective IKCa (intermediate-conductance calcium-activated potassium channel) inhibitor TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole; −50.7%) and the voltage-gated potassium channel inhibitor 4-aminopyridine (−40.8%). In isolated aortic smooth muscle, PPT strongly enhanced the cyclic GMP content (+144%) and Rp-8-Br-cGMP largely reduced the PPT-dependent calcium signal (−80.8%). Conclusions ERα receptor stimulation in rat aortic smooth muscle evokes a PKG-signalling pathway, likely triggering relaxation by BKCa and IKCa channel opening.

Current knowledge of the effect of tibolone on the breast and uterus: an extract from the guidelines for the use of tibolone in South Africa

BackgroundTibolone is an analogue of the progestin, norethynodrel. After ingestion, it is converted to three metabolites, namely 3 alpha and 3 beta hydroxytibolone which have oestrogenic effects, and delta 4 isomerase, which has progestogenic and androgenic properties. Both the oestrogenic metabolites bind to the alpha oestrogen receptor, but not the beta oestrogen receptor, whilst the delta 4 isomer binds to the alpha and beta oestrogen, the progestogen and the androgen receptors. Tibolone also is a sulphatase inhibiter, blocking conversion of oestrone sulphate to oestrone, as well as stimulating local sulphotransferase activity. In contrast to other forms of postmenopausal hormonal therapy, it decreases sex hormone binding globulin and hence increases circulating free testosterone, and thereby further adding to its androgenicity. Tibolone significantly decreases vasomotor symptoms, mood disorders, insomnia, bone loss, vaginal atrophy. It has a favourable impact on the cardiovascular system and minimal i...

Estrogen receptor beta participate in the regulation of metabolizm of extracellular matrix in estrogen alpha negative breast cancer.

Estrogen receptor beta participate in the regulation of metabolizm of extracellular matrix in estrogen alpha negative breast cancer.

Diet and Expression of Estrogen Alpha and Progesterone Receptors in Malignant Mammary Tissue

Estrogen receptor (ER) and/or progesterone receptor (PR) expression has been associated with more favorable breast cancer prognosis. Results on the differential association of diet with ER and/or PR positive and negative tumors have been inconclusive. In a large case-control study conducted in Athens, Greece, we investigated whether diet is associated with the expression of ER-alpha or PR in mammary tumors of 421 women with histologically confirmed breast cancer. Diet was assessed through an extensive food frequency questionnaire and results were analyzed using multiple logistic regression. After controlling for non-nutritional variables and mutually adjusting for energy-generating nutrients and ethanol, carbohydrate intake was inversely associated with ER-alpha (P = 0.04) and PR (P = 0.10) expression. The odds ratios (OR) per one standard deviation increment were 0.69 with 95% confidence interval (95% CI) 0.48-0.98 for ER-alpha and 0.72 (95% CI 0.49–1.07) for PR expression. No consistent or statistically significant associations were noted for any of the other energy-generating nutrients or food groups examined. Although in these data no strong relations of qualitative aspects of diet with hormone receptor expression in breast cancer tumors were evident, the inverse association of carbohydrate intake with ER-alpha, and perhaps PR, expression merits further study in future investigations.

Expression of oestrogen and progesterone receptors in canine sebaceous gland tumours

Sebaceous gland oestrogen alpha (ERalpha) and progesterone (PR) receptor expression was examined immunohistochemically in 26 and 32 dogs respectively with sebaceous gland hyperplasia/adenomas, epitheliomas and carcinomas, and in the glands of 10 healthy controls. The mean percentage of ERalpha positive nuclei in control sebaceous glands was 21.31% compared with 11.5% in hyperplasia/adenoma-type lesions, although these values were not statistically different. In sebaceous gland epitheliomas and carcinomas, positive basal cells represented 7.86% and 3.53% of neoplastic cells respectively and these mean percentages were significantly lower in epitheliomas (P < 0.024) and carcinomas (P < 0.015) than in controls. The mean percentage of PR-positive nuclei in control sebaceous glands was 23.96%, similar to the 22.07% found in hyperplasia/adenoma-type lesions. In sebaceous gland epitheliomas and carcinomas, positive cells were scarce and represented 13.5% and 4.06% of neoplastic cells respectively. Differences in the percentage of positive cells between normal and pathological glands reached statistical significance for carcinomas (P < 0.043). In the control group there was greater PR (P < 0.001) and ERalpha expression (P < 0.014) in sebaceous glands in female dogs. The PR and ERalpha immunoreactivity in each category of neoplastic lesions could not be analysed because sample size was too small but when all the sebaceous gland tumours were grouped and analysed, no sex difference was found. The results suggest that oestrogen and progesterone receptor expression is reduced in some canine sebaceous gland tumours. These changes may represent a contributing factor for tumour growth or simply be a consequence of tumour progression.

The effect of Telmisartan on collagen biosynthesis depends on the status of estrogen activation in breast cancer cells

PPAR-γ and estrogen receptor belong to a family of nuclear hormone receptors that were shown to affect transcriptional activity of each other. The angiotensin II type 1 receptor antagonist Telmisartan is a well known PPAR-γ ligand. The effect of Telmisartan-induced PPAR-γ activation on collagen biosynthesis was studied in the estrogen-dependent (MCF-7 cells expressing α and β receptors) and estrogen-independent (MDA-MB 231, expressing only β receptor) cell lines. We have found that the presence of estrogen in growth medium (2 nM) augmented collagen biosynthesis in both cell lines. An addition to the growth medium of PPAR-γ agonist, Telmisartan, but not rosiglitazone or clofibrat, other PPAR-γ agonists, induced inhibition of collagen biosynthesis in MCF-7 cells, cultured in the presence of estrogen, while it had no effect on collagen biosynthesis in MDA-MB-231 cells. On the other hand, Telmisartan induced stimulation of collagen biosynthesis in MCF-7 cells cultured in the absence of estrogen (or in conditions of estrogen receptor removal by ICI 182-780-dependent degradation) and had no effect on similarly cultured MDA-MB-231 cells. The effect of Telmisartan on collagen biosynthesis was found specific for PPAR-γ and not for angiotensin II type 1 since Losartan (specific antagonist of angiotensin II type 1 receptor) in the presence of estradiol did not induce inhibition of this protein in MCF-7 cells. The mechanism of the inhibition was found at the level of NF-kB (known inhibitor of collagen gene expression) and MAPK signaling. PPAR-γ ligands stimulated expression of NF-kB, while they inhibited expression of p-38 but not ERK1/ERK2. The data suggest that the effect of Telmisartan on collagen biosynthesis in breast cancer cells depends on the status of estrogen receptor activation and the inhibitory effect of Telmisartan on the process requires functional alpha estrogen receptor.

Immunohistochemical Localization of the Progesterone and Oestrogen α Receptors in the Uterine Horns of the African Giant Rat (Cricetomys gambianus)

The present study investigated the immunolocalization of the progesterone and oestrogen alpha receptors in the uterine horns of the African giant rat during the oestrous cycle. The progesterone and oestrogen alpha receptors were demonstrated in various cellular constituents of the endometrium, myometrium and perimetrium. The intensity of progesterone and oestrogen alpha receptor immunostaining in the endometrial and myometrial layers of the uterine horns varied during the oestrous cycle. The intensity of oestrogen alpha receptor immunoreactivity in the luminal epithelium was high during pro-oestrus, oestrus and dioestrus. Progesterone and oestrogen alpha receptor immunoreactivity in the endometrial epithelia was absent during metoestrus. Moderate to strong immunostaining for the progesterone and oestrogen alpha receptors was demonstrated in the myometrial smooth muscle cells during pro-oestrus, oestrus and dioestrus. The intensity of progesterone and oestrogen alpha receptor immunostaining in the myometrial smooth muscle cells was low during metoestrus. Stromal cells in the perimetrium consistently expressed progesterone and oestrogen alpha receptor immunoreactivity throughout the oestrous cycle. The findings of the study indicate that in the giant rat the immunolocalization of the progesterone and oestrogen alpha receptors, in endometrial and myometrial regions of the uterine horns, varies during the oestrous cycle.

Hyperactivated NF-κB and AP-1 Transcription Factors Promote Highly Accessible Chromatin and Constitutive Transcription across the Interleukin-6 Gene Promoter in Metastatic Breast Cancer Cells

Interleukin-6 (IL-6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes the response to hormones and to chemotherapeutics. We explored transcription mechanisms involved in differential IL-6 gene expression in breast cancer cells with different metastatic properties. In weakly metastatic MCF7 cells, histone H3 K9 methylation, HP1 binding, and weak recruitment of AP-1 Fra-1/c-Jun, NF-kappaB p65 transcription factors, and coactivators is indicative of low chromatin accessibility and gene transcription at the IL-6 gene promoter. In highly metastatic MDA-MB231 cells, strong DNase, MNase, and restriction enzyme accessibility, as well potent constitutive transcription of the IL-6 gene promoter, coincide with increased H3 S10 K14 phosphoacetylation and promoter enrichment of AP-1 Fra-1/c-Jun and NF-kappaB p65 transcription factors and MSK1, CBP/p300, Brg1, and Ezh2 cofactors. Complementation, silencing, and kinase inhibitor experiments further demonstrate involvement of AP-1 Fra-1/c-Jun and NF-kappaB p65/RelB members, but not of the alpha estrogen receptor in promoting chromatin accessibility and transcription across the IL-6 gene promoter in metastatic breast cancer cells. Finally, the natural withanolide Withaferin A was found to repress IL-6 gene transcription in metastatic breast cancer cells upon dual inhibition of NF-kappaB and AP-1 Fra-1 transcription factors and silencing of IL-6 promoter chromatin accessibility.

Up‐regulation of the inflammatory‐reparative phenotype in human prostate carcinoma

Recent studies have underlined the role of tumor cells in the endogenous synthesis of pro-inflammatory molecules. We tested whether malignant progression in prostate cancer was associated with the activation of a phenotype typical of the innate immune system. The expression of a set of molecules involved in tissue inflammation and repair was measured by real-time PCR and Western blot analysis in prostate samples in the absence or slight presence of a detectable leukocyte infiltrate. Whole tumor and non-tumor samples were analyzed in addition to laser-capture microdissected tumor and host epithelium. Receptor for advanced glycation end products, purine receptor, inducible enzymes cyclooxygenase-2 and nitric oxide synthase-2, pentraxin-3 and growth-survival factor receptors such as epithelial growth factor and estrogen alpha and beta receptors were all studied. A global survey approach showed an up-regulation in tumor samples of all of the studied genes, with the exception of ERbeta. A laser-capture microdissection approach highlighted over-expression of pro-inflammatory molecules in each tumor sample examined. Nuclear translocation of nuclear factor-kB subunit p65 was observed in tumor tissues. These data support the evidence that molecules typical of the innate immune system, similar to that of activated leukocytes, are produced by prostate epithelial cells and that their expression is up-regulated in malignant cells. We suggest that the observed pro-inflammatory and repair process activation may represent an important molecular mechanism in the progression of prostate cancer.