Evaluation Of Estrogen Receptor Research Articles

Estrogen/Progesterone Receptor Negativity and HER2 Positivity Predict Locoregional Recurrence in Patients With T1a,bN0 Breast Cancer

Data have suggested that the molecular features of breast cancer are important determinants of outcome; however, few studies have correlated these features with locoregional recurrence (LRR). In the present study, we evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of LRR in patients with lymph node-negative disease and tumors < or = 1cm, because these patients often do not receive adjuvant chemotherapy or trastuzumab. The data from 911 patients with stage T1a,bN0 breast cancer who had received definitive treatment at our institution between 1997 and 2002 were retrospectively reviewed. We prospectively analyzed ER/PR/HER2 expression from the archival tissue blocks of 756 patients. These 756 patients represented the cohort for the present study. With a median follow-up of 6.0 years, the 5- and 8-year Kaplan-Meier LRR rate was 1.6% and 5.9%, respectively, with no difference noted in those who underwent breast conservation therapy vs. mastectomy (p=.347). The 8-year LRR rates were greater in the patients with ER-negative (10.6% vs. 4.2%, p=.016), PR-negative (9.0% vs. 4.2%, p=.009), or HER2-positive (17.5% vs. 3.9%, p=0.009) tumors. On multivariate analysis, ER-negative and PR-negative disease (hazard ratio, 2.37; p=.046) and HER2-positive disease (hazard ratio, 3.13, p=.016) independently predicted for LRR. Patients with ER/PR-negative or HER2-positive T1a,bN0 breast cancer had a greater risk of LRR. Therapeutic strategies, such as the use of chemotherapy and/or anti-HER2 therapies, should be considered for future clinical trials for these patients.

Molecular cloning and characterization of ligand- and species-specificity of amphibian estrogen receptors

Estrogens are essential for normal reproductive activity in both males and females as well as for ovarian differentiation during a critical developmental stage in most vertebrates. To understand the molecular mechanisms of estrogen action and to evaluate estrogen receptor ligand interactions in amphibians, we isolated cDNAs encoding the estrogen receptors (ERα and ERβ) from the Japanese firebelly newt ( Cynops pyrrhogaster), Tokyo salamander ( Hynobius tokyoensis), axolotl ( Ambystoma mexicanum), and Raucous toad ( Bufo rangeri). Full-length amphibian ER cDNAs were obtained using 5′ and 3′ rapid amplification of cDNA ends. The predicted amino acid sequences of these amphibian ERs showed a high degree of amino acid sequence identity (over 70%) to each other. We analyzed the relationships of these amphibian ER sequences to other vertebrate ER sequences by constructing a phylogenetic tree. We verified that these were bona fide estrogen receptors using receptor dependent reporter gene assays. We analyzed the effects of natural estrogens, ethinylestradiol, and DDT and its metabolites on the transactivation of the four amphibian species listed above, and Xenopus tropicalis ERs and found that there were species-specific differences in the sensitivity of these ERs to hormones and environmental chemicals. These findings will expand our knowledge of endocrine-disrupting events in amphibians.

Menopausal Hormone Therapy, Hormone Receptor Status, and Lung Cancer in Women

Gender differences in lung cancer incidence and outcome suggest a potential role for reproductive hormones. However, observational studies regarding menopausal hormone therapy use and lung cancer have given mixed results. Some have associated hormone therapy use with increased lung cancer risk, while others have shown no effect or found lower lung cancer risk in hormone therapy users. Against this background the Women's Health Initiative (WHI) randomized controlled trial evaluating conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in postmenopausal women identified an increase in malignancies in the hormone therapy group during the post intervention period. Post hoc analyses identified a statistically significant increase in deaths from lung cancer for women in the hormone group largely related to effects on non-small cell lung cancer (NSCLC). The NSCLCs were more commonly poorly differentiated and were diagnosed at a metastatic stage, suggesting a hormone effect on already established lung cancer growth. Ongoing preclinical and clinical analyses have identified estrogen receptors in the nucleus and cytoplasm of lung tissue and lung cancers. More recently, intriguing associations among estrogen receptor expression, lung cancer histology, clinical prognosis, and epidermal growth factor receptor (EGFR) mutations have been reported. The WHI clinical findings should be integrated into risk-benefit discussion with women considering combined hormone therapy use. In addition, the findings, together with ongoing studies evaluating estrogen receptor status and function, support further efforts to develop lung cancer intervention strategies targeting estrogen receptor expression.

Cross-Talk between Estrogen Receptor and Epidermal Growth Factor Receptor in Head and Neck Squamous Cell Carcinoma

This study aimed to characterize estrogen receptor expression and signaling in head and neck squamous cell carcinoma (HNSCC) cell lines and patient tissues, and to evaluate estrogen receptor and epidermal growth factor (EGF) receptor (EGFR) cross-activation in HNSCC. Estrogen receptor expression and signaling in HNSCC cell lines were assessed by immunoblotting. In vitro proliferation and invasion were evaluated in HNSCC cell lines in response to estrogen receptor and EGFR ligands or inhibitors. Estrogen receptor and EGFR protein expression in patient tissues was assessed by immunohistochemical staining. Phospho-mitogen-activated protein kinase (P-MAPK) levels were significantly increased following combined estrogen and EGF treatment. Treatment of HNSCC cells with estrogen and EGF significantly increased cell invasion compared with either treatment alone, whereas inhibiting these two pathways resulted in reduced invasion compared with inhibiting either pathway alone. EGFR (P = 0.008) and nuclear estrogen receptor alpha (ER alpha(nuc); P < 0.001) levels were significantly increased in HNSCC tumors (n = 56) compared with adjacent mucosa (n = 30), whereas nuclear estrogen receptor beta (ER beta(nuc)) levels did not differ (P = 0.67). Patients with high ER alpha(nuc) and EGFR tumor levels had significantly reduced progression-free survival compared with patients with low tumor ER alpha(nuc) and EGFR levels (hazards ratio, 4.09; P = 0.01; Cox proportional hazards). In contrast, high ER beta(nuc) tumor levels were not associated with reduced progression-free survival alone or when combined with EGFR. ER alpha and ER beta were expressed in HNSCC, and stimulation with estrogen receptor ligands resulted in both cytoplasmic signal transduction and transcriptional activation. Estrogen receptor and EGFR cross-talk was observed. Collectively, these studies indicate that estrogen receptor and EGFR together may contribute to HNSCC development and disease progression.

Immunohistochemical detection of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression in breast carcinomas

Fine-needle aspiration (FNA) is a rapid and accurate procedure for the detection of breast carcinomas. The evaluation of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression by immunohistochemistry (IHC) is performed routinely on formalin-fixed, paraffin-embedded needle-core (NC) or excision tissue block (TB) preparations, according to the American Society of Clinical Oncology/College of American Pathologist guidelines. In this retrospective study, the authors compared expression levels of ER, PR, and HER2 in ethanol-fixed BC FNA cell block (CB) samples with expression levels in formalin-fixed NC and TB samples. Forty-one breast carcinoma CB samples with concurrent or subsequent NC and TB samples were identified. Patients who had received neoadjuvant or adjuvant chemotherapy were excluded. CB samples initially were fixed in 50% ethanol (4-12 hours), and this was followed by formalin fixation (minimum, 6 hours). NC samples were placed promptly in formalin for a minimum of 6 hours. Within 4 to 8 hours, TB samples were fixed in formalin for 6 to 48 hours. Fluorescence in situ hybridization (FISH) results were also compared. IHC for ER on alcohol-fixed CB samples had good correlation with NC and TB samples. PR results on TB samples had excellent agreement with NC samples. A higher discordance rate wais observed when PR results were compared between CB samples and NC samples. HER2 detection on ethanol-fixed CB samples resulted in a higher rate of positive and equivocal staining than NC or TB samples. HER2 IHC on TB samples demonstrated better correlation with FISH results than CB or NC samples. Alcohol fixation did not affect ER results in breast carcinoma, but it may alter tumor cell PR antigenicity. The authors concluded that CB samples could be used to triage patients for tamoxifen therapy, but they are not reliable for the assessment of HER2 status; therefore, CB results should be correlated with results from NC or TB samples.

Estrogen Receptor Immunohistochemistry for Confirmation of Sentinel Lymph Node Metastasis in Cases With Equivocal Cytokeratin Positivity

Differentiation of true metastases from cytokeratin (CK)-positive nonepithelial cells by immunohistochemistry occasionally may be difficult in the evaluation of sentinel lymph nodes (SLNs) for occult breast carcinoma metastases. In this study, we evaluated estrogen receptor (ER) immunostaining superimposed on CK as a method for the confirmation of metastasis when CK immunostaining alone was equivocal. We performed sequential ER staining on previously CK-stained slides on 15 axillary SLNs from breast cancer patients: 5 SLNs with known metastatic carcinoma (positive controls), 6 known negative SLNs (negative controls), and 4 test cases (3 SLNs in which CK-positive cells were equivocal for malignancy and 1 SLN in which metastasis was obvious, but contained focal weakly CK-positive signet ring cells). The primary tumor in all cases expressed ER in >50% of cells. Only 3 of 5 positive controls showed metastatic cells with dual CK/ER staining. CK-positive reticulum cells in all negative controls were ER negative. Three test cases showed dual CK/ER staining in the equivocal cells. The case with signet ring cells showed strong ER staining in the nonsignet ring cells and weaker staining in the signet ring cells. We conclude that dual CK/ER staining can be useful in SLNs when CK staining alone is equivocal, particularly when the primary tumor is known to have high expression of ER. Although dual ER/CK positivity helps to confirm metastasis, negative ER staining does not exclude metastatic disease.

Estrogen Receptor Expression in Cutaneous Melanoma

To evaluate estrogen receptor (ER) expression in human melanoma tissues and in the adjacent healthy skin with the aim of explaining whether the ERalpha:ERbeta expression ratio has a role in neoplastic progression. Prospective study. Department of Dermatology, University of Florence, Florence, Italy. Patients Fourteen patients, 12 with cutaneous melanoma (6 women and 6 men) and 2 with melanocytic nevi (1 woman and 1 man). Using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical analysis, we analyzed ERalpha and ERbeta messenger RNA (mRNA) and ERbeta protein expression in cutaneous melanoma and in the healthy skin surrounding the lesions. All melanocytic lesions expressed detectable levels of ERalpha and ERbeta mRNA as well as ERbeta protein. Dividing melanoma cases into 2 groups according to Breslow thickness, we found lower ERalpha and ERbeta mRNA levels and lower ERbeta protein levels in thicker, more invasive tumors. These observations suggest a role for ERs in the metastatic process of melanoma cells, pointing at the possibility of using ERbeta expression as a prognostic indicator of melanoma. The possibility of distinguishing proliferative melanomas, which are associated with dismal prognosis, from the so-called dormant melanomas opens up novel avenues in tailoring individual treatments, as already happens for other tumors.

Synthesis and Evaluation of Estrogen Receptor β -Selective Ligands: Fluoroalkylated Indazole Estrogens

It is important to identify selective ligands for the estrogen receptor subtypes ERα or ERβ to evaluate them as pharmaceutical targets in breast cancer. To develop ERβ-selective ligands as PET imaging agents, a series of aryl indazole estrogen analogues substituted at the C3 position with fluoroethyl and fluoropropyl groups were synthesized and evaluated for their relative binding affinities and selectivities for ERα vs ERβ. The fluoroethylated indazole estrogen (FEIE, 1i) and fluoropropylated indazole estrogen (FPIE, 1h) showed 41fold and 17-fold ERβ/ERα selectivity, respectively. However, their binding affinities to ERα and ERβ were very low.

Evaluation of estrogen receptor α and β and progesterone receptor expression and correlation with clinicopathologic factors and proliferative marker Ki-67 in breast cancers

To elucidate the molecular profile of hormonal steroid receptor status, we analyzed ER-alpha, ER-beta, and PGR mRNA and protein expression in 80 breast carcinomas using reverse transcriptase polymerase chain reaction (RT-PCR), quantitative RT-PCR, and immunohistochemical analysis. Qualitative analysis revealed positive expression of ER-alpha, ER-beta, and PGR mRNA in 48%, 59%, and 48% of the breast carcinomas, respectively. ER-alpha, ER-beta, and PGR transcript overexpression was observed in 51%, 0%, and 12% of the cases, respectively, whereas moderate or strong protein expression was detected in 68%, 78%, and 49% of the cases, respectively. Tumor grade was negatively correlated with transcript and protein levels of ER-alpha (P = .0169 and P = .0006, respectively) and PGR (P = .0034 and P = .0005, respectively). Similarly, proliferative index Ki-67 was negatively associated with transcript and protein levels of ER-alpha (P = .0006 and P < .0001, respectively) and PGR (P = .0258 and P = .0005, respectively). These findings suggest that ER-alpha and PGR expression are associated with well-differentiated breast tumors and less directly related to cell proliferation. A significant statistical difference was observed between lymph node status and ER-beta protein expression (P = .0208). In ER-alpha-negative tumors, we detected a correlation between ER-beta protein expression and high levels of Ki-67. These data suggest that ER-beta could be a prognostic marker in human breast cancer.

A comparison between the novel rabbit monoclonal antibodies (SP1 and B644) and mouse antibodies for evaluating estrogen receptor in breast tumors

BACKGROUND: A novel generation of rabbit monoclonal antibodies has been released recently for estrogen (ER) and progesterone (PR) receptor evaluation in breast cancer by immunohistochemistry. Aims: We compared novel rabbit monoclonal antibodies anti-ER SP1 (LabVision®) and B644 (Cell Marque®) to mouse monoclonal antibodies 1D5 (Dako®) and 6F11 (Novocastra®) using a tissue microarray of breast carcinomas. METHODS: Two cylinders (2 mm diameter) of formalin-fixed paraffin embedded tissue were obtained from 24 invasive breast carcinomas and immunostained by using the anti-ER rabbit and mouse antibodies and the streptavidin-biotin detection system (Biogenex®). Immunostaining was evaluated considering positive those tumors in which more than 10% of the tumor cell nuclei stained. The stain intensity was also evaluated as weak (1), moderate (2), and strong (3). Results: Both rabbit antibodies against ER have similar staining pattern to each other and also to 6F11, but significantly stronger scores compared to mouse 1D5. The rabbit antibodies allow better cost/benefit because of higher working dilutions compared to mouse antibodies using the same procedure. CONCLUSION: The new rabbit antibodies against ER are highly sensitive and reliable in clinical and research immunohistochemical testing of breast carcinomas.

Assessment of Two Automated Imaging Systems in Evaluating Estrogen Receptor Status in Breast Carcinoma

Immunohistochemical staining for estrogen receptor (ER) status is widely used in the management of breast cancer. These stains have traditionally been scored manually, which results in generally good agreement among observers when the cases are strongly positive. However, significant interobserver and intraobserver differences in scoring can occur in borderline or weakly staining cases. Recently, automated systems have been proposed to provide a more sensitive and objective method of ER quantification. The ChromaVision Automated Cellular Imaging System and the Applied Imaging Ariol SL-50 quantify the color intensity of the immunoreactive product. To assess the accuracy of these 2 automated systems and to compare them to one another and to manual scoring, we performed immunostaining for ER on 64 cases of breast cancer. The percentages of positive cells were scored manually by 4 pathologists and by the 2 imaging systems. A discrepancy in scoring was defined as that which resulted in the reclassification of a case from negative to positive or vice versa. Our results showed significant agreement between the 2 automated systems. When automated scores were compared with the manual scores, only 5 of the 64 cases (7%) were discrepant. In 4 of these, the percentage of cells staining for ER was low (0% to 20%). Overall, the 2 systems were comparable, and discrepant results were most frequently seen when analyzing tumors with low levels of ER positive cells.

O-33 Is the difference between tamoxifen and anastrozole in adjuvant trials applicable for primary endocrine therapy of early operable primary breast cancer in the elderly?

In the present study, we aimed to evaluate estrogen receptor ER-alpha status in 61 breast cancer cases using Sp1 and 1D5 monoclonal antibodies. Tissue array platforms were generated containing samples of breast cancer and positive controls that were assayed by immunohistochemistry applying monoclonal primary antibodies anti-ER alpha, SP1 and 1D5. We noted a high concordance rate (96.7%) between the referred antibodies. Moreover, we calculated the Kappa factor (0.921), indicating that 1D5 and SP1 provided overlapping ERα expression results. Indeed, we observed controversial results only in 2 samples studied, which were ER-negative when stained with 1D5 and ER-positive when assessed with SP1. Total concordance of PS was obtained (Pearson and intraclass CF, 0.7351 and 0.6193, respectively). However, concordance between the antibodies seems to be more accurate in higher PS values. An excellent IS correlation between antibodies was observed throughout the population (Spearman's CF, ρ = 0.9150). Following the Allred score, 17 out of 42 positive BC samples diverged, with 1D5 always pointing to weaker staining than SP1. When calculating Spearman's CF of Total Score (TS) within the population, an excellent correlation between both the antibodies (ρ = 0.9238) was noted. Nonetheless, the results were less concordant among the BC-positive cases (ρ = 0.7743). Indeed, 20 samples were differentially classified using the antibodies (only 3 had higher TS with 1D5). Considering the mean TS of all samples or of invasive ductal carcinoma, SP1 provided higher scores than 1D5 (p < 0.05). We recommend the use of the anti-ER RMAb SP1 due to the high probability that the BC ERα status can be determined accurately as the reagent provides higher IS. Therefore, the A-score was higher than the MMAb 1D5. Ultimately, higher IS and A-score decrease the possibility of ERα status misinterpretation and, consequently, inappropriate BC treatment that would compromise the patient's quality of life and overall survival. We recommend the use of anti-ER RMAb SP1 due to the high probability that the BC ER status can be determined accurately as the reagent provides higher IS, therefore higher A-score, than the MMAb 1D5.

Efficacy of Selective Estrogen Receptor Modulators in Nude Mice Bearing Human Transitional Cell Carcinoma

To evaluate estrogen receptors as a therapeutic target for human bladder cancer. The ability of the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene to inhibit 5637 human transitional cell carcinoma cell proliferation was determined in vitro and in xenograft studies using 5637 cells in female athymic BALB/c nu/nu mice. Treatment with tamoxifen, raloxifene, or the pure antiestrogen ICI 182,780 inhibited proliferation of 5637 cells in vitro. In the first xenograft study, raloxifene (10, 100, or 1000 microg/day) administered by oral gavage inhibited the growth of tumors compared with placebo or untreated controls (P <0.05). In a second experiment, tamoxifen (8.3, 125, or 1250 microg/day) delivered by time-release pellet inhibited tumor growth compared with placebo-treated controls (P <0.01). A comparison study in which tamoxifen (8.3 or 125 microg/day) or raloxifene (100 microg/day) was administered by slow-release pellet demonstrated that both SERMs reduced growth compared to placebo-treated controls (P <0.05), with comparable effectiveness. There was no detectable tumor in 17 of 30 treated mice. In all studies, average tumor volumes in SERM-treated animals declined over the course of treatment. Selective estrogen receptor modulators inhibit the growth of 5637 transitional cell carcinoma cell xenografts, supporting the rationale to evaluate these agents as targeted therapeutics for patients with urothelial carcinoma.

Ontogeny of androgen and estrogen receptor expression in porcine testis: Effect of reducing testicular estrogen synthesis

Reducing endogenous estrogen leads to increased proliferation of porcine Sertoli cells during the first 2 months of life. The resulting increase in porcine Sertoli cell numbers is maintained through puberty. The reduced estrogen appears to be the direct hormonal mediator because essentially no changes are observed in other hormones. However, the mechanism for this effect on Sertoli cell proliferation is unknown. The objective of these studies was to evaluate estrogen receptors α and β (ESR1 and ESR2) in conjunction with androgen receptor (AR) on Sertoli cells and other testicular cell types, as an initial step toward understanding how reduced estrogen leads to increased Sertoli cell numbers. Testis sections from treated animals (aromatase inhibition to decrease endogenous estrogen beginning at 1 week of age) and from littermate controls treated with vehicle were subjected to immunocytochemical labeling for ESR1, ESR2, and AR. Three observers scored Sertoli cells, interstitial cells, peritubular myoid cells, and germ cells for intensity of labeling (0: absent; 1+: weak; 2+: moderate; or 3+: strong labeling). AR in Sertoli cells was readily detected at 1 week of age, was very faint in 2-month vehicle controls, and labeling appeared to increase in 3-month vehicle controls. AR in Sertoli cells, interstitial cells, and apparently germ cells was increased in treated animals at 2 months of age compared with the vehicle controls. This increase was confirmed in western blots. ESR1 and ESR 2 were clearly present in Sertoli cells from 1-week-old animals; ESR in Sertoli cells generally decreased with age with the decrease more apparent for ESR2. ESR1 in Sertoli cells and peritubular myoid cells exhibited some treatment-related effects but reduction of endogenous estrogen did not appear to affect ESR2 in the boar testis. The observed alterations in AR and ESR1 may mediate the increases in Sertoli cell proliferation following inhibition of endogenous estrogen production or may reflect the altered function of the Sertoli cells and peritubular myoid cells.

Molecular cloning of estrogen receptor alpha (ERα; ESR1) of the Japanese giant salamander, Andrias japonicus

Estrogens are essential for normal reproductive activity in females and males and for ovarian differentiation during a critical developmental stage in many vertebrates. To understand the molecular mechanisms of estrogen action and to evaluate estrogen receptor ligand interactions in the Japanese giant salamander ( Andrias japonicus), we isolated cDNA encoding the estrogen receptor (ER) from the liver. A full-length Japanese giant salamander ER cDNA (jgsER) was obtained using 5′ and 3′ rapid amplification cDNA ends (RACE). The deduced amino acid sequence of the jgsER showed high identity to the Xenopus ERα (ESR1) (77.7%). We have applied both the conventional ERE-luciferase reporter assay system and the GAL4-transactivation system to characterize this receptor. In two different transient transfection assay systems using mammalian cells, the jgsER protein displayed estrogen-dependent activation of transcription. The GAL4-transactivation system showed about 10-fold greater activity of the estrogen receptor by hormone when compared to the conventional ERE-luciferase reporter assay system. Tissue distribution of ERα mRNA was examined and kidney, ovary and liver exhibited expression. This is the first isolation of an estrogen receptor from a salamander and also is the first functional cDNA obtained from the Japanese giant salamander, an endangered species considered a special natural monument of Japan.

Immunohistochemical Evaluation of Estrogen Receptor β Expression in Calf Prostates with Squamous Metaplasia

Immunohistochemical Evaluation of Estrogen Receptor β Expression in Calf Prostates with Squamous Metaplasia

Exemestane in advanced and recurrent endometrial carcinoma. A phase II study

5042 Background: Most entrometrial adenocarcinomas of the endometrioid type express estrogen receptors and are potentially hormone sensitive. The aim of this phase II study was to evaluate the responsiveness of these tumors to treatment with Exemestane, an aromatase inhibitor. Methods: So far, 31 patients have been recruited to this ongoing study. Patients had to have a measurable tumor. Evaluation of response by CT was performed every 3 months. Evaluation of estrogen receptors (ER) was performed by immunohistochemistry and was positive in 17 patients, negative in 5 and not performed in 6 of the 28 patients evaluable for response. Treatment was given with Exemestane 25 mg orally daily. Results: Radiotherapy had been given as part of the initial therapy to 16 patients. Before inclusion into the study, 22 patients had received chemotherapy and 7 of these had also received hormonal treatment with gestagens for relapse. Response to Exemestane treatment was evaluable in 28 patients. In 17 patients with ER positive tumors, 1 showed a complete response, 1 partial response and 6 have had stable disease for 3+ months (3 patients), 6+ months (2) and 9+ months (1). The treatment was well tolerated with no major toxicity. Updated response rates will be presented. Conclusions: Treatment with Exemestane orally showed effect in patients with ER positive tumors in this heavily pre-treated group of patients with endometrioid adenocarcinoma of the endometrium. No significant financial relationships to disclose.

Gender difference in the activity but not expression of estrogen receptors α and β in human lung adenocarcinoma cells

The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer. We evaluated estrogen receptor (ER) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts. Full-length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha. Although estradiol (E(2)) binding was similar, E(2) stimulated proliferation only in cells from females, and this response was inhibited by anti-estrogens 4-hydroxytamoxifen (4-OHT) and ICI 182,780. In contrast, E(2) did not stimulate replication of lung adenocarcinoma cells from males and 4-OHT or ICI did not block cell proliferation. Similarly, transcription of an estrogen response element-driven reporter gene was stimulated by E(2) in lung adenocarcinoma cells from females, but not males. Progesterone receptor (PR) expression was increased by E(2) in two out of five adenocarcinoma cell lines from females, but none from males. E(2) decreased E-cadherin protein expression in some of the cell lines from females, as it did in MCF-7 breast cancer cells, but not in the cell lines from males. Thus, ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells. On the other hand, coactivator DRIP205 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells. DRIP205 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males.

Estrogen receptor knockout mice as a model for endocrine research.

The biological effects of estrogen in mammalian target tissues are important for multiple organ systems including the male and female reproductive tract and the neuroendocrine, skeletal, and cardiovascular systems. Numerous physiological effects of estradiol are modulated by the estrogen receptor (ER), a Class I member of the nuclear receptor superfamily. However, more recent studies have also implicated nongenomic effects of estrogen, which may involve a membrane-binding site. The two forms of the ER are the classical estrogen receptor-alpha (ERalpha) and the more recently discovered estrogen receptor-beta (ERbeta). Gene-targeting techniques were used to generate mice lacking either functional ERalpha (alphaERKO), ERbeta (betaERKO), or both ERs (alphabetaERKO) to provide a model for evaluating estrogen receptor action. These knockout models provide a unique tool to study the effects of estrogen in the context of the whole animal and to discern the role of each ER in various tissues. The reproductive phenotypes as well as some of the nonreproductive phenotypes of the different ERKO models are summarized.

Estrogen levels and estrogen receptors in patients with stress urinary incontinence and pelvic organ prolapse

Objectives: To investigate the histologic characteristics of tissues presumed to be the cause of urinary stress incontinence and pelvic organ prolapse. Methods: Cardinal ligament and uterosacral ligament samples were obtained from 73 women undergoing hysterectomy. The evaluation of estrogen receptors (ERs) by immunohistochemical staining was semi-quantitative. Serum estrogen was determined by ELISA. Statistical analyses were performed by the independent-sample t-test and one-way ANOVA. Results: Serum estradiol levels and ER values in the premenopausal women with pelvic organ prolapse were significantly lower than in the control group ( P<0.01). A positive correlation was found between ERs and the number of postmenopausal years ( P<0.01). ER values were similar in the cardinal and uterosacral ligaments. Conclusions: Serum estrogen levels and ER values are significantly lower in the uterine ligaments of premenopausal women with pelvic organ prolapse, and there was a positive correlation between ER values in the uterine ligaments and the duration of postmenopausal years. Serum estrogen levels and ER values were similar in the cardinal ligament and the uterosacral ligament.