The role of estrogen receptors in breast cancer metastasis

It has long been appreciated that the estrogen receptor (ER) plays an important role in the biology of breast cancer. It is an accepted factor predicting favorable disease outcome and treatment response, and as such is generally considered to represent a good prognostic marker in breast cancer. In this review we present data suggesting that the ER may also play a pivotal role in the metastatic behavior of breast cancer, and present an argument that the up-regulation of ER and/or the selection of specific ER mutations are early events important for facilitating tumor progression. Thus, ER could serve dual roles in breast cancer, acting as a bad prognostic marker later in the disease process.     

Reduction of estrogen and prolactin receptors in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumor by high doses of estrogen

Daily injections of 100 μg17 β-estradiol, or 250 μg tamoxifen, for 10 days led to a regression of the 7,12-dimenthylbenz(a)anthracene (DMBA)-induced rat mammary tumor. Estrogen receptor (ER), progesterone receptor (PgR), and prolactin receptor (PRL-R) in the regressed tumor were significantly reduced in the estrogen-treated rats. ER and PRL-R were low but PgR increased significantly in the tumor of the tamoxifen-treated rats. A single administration of 100 μg estradiol induced a transient decrease of ER and PRL-R, and an increase of PgR, in the DMBA-tumor. Similar decreases in ER and PRL-R and the increase of PgR were observed 8 hours after the 5th injection of 100 μg estradiol—a time when the tumor had already regressed. These results suggest that high dose-estrogen has a direct inhibitory effect on the concentration of both ER and PRL-R in the DMBA-tumor, and that this effect might be accumulative with repeated administrations. It is unlikely that the inhibition of the estrogenic effect caused by loss of ER is the sole mechanism of the regression of the DMBA-tumor, since the increased synthesis of PgR as a marker of estrogen action was observed even after the ER-reduction and tumor-regression.     

Cytohistochemical studies on estrogen receptors of breast cancer tissue using an immunoperoxidase technique

The estrogen receptors (ER) in breast cancer tissues were investigated in 122 patients using an immunoperoxidase method. ER (+) were evident in 77 of 122 patients (63.1 per cent). If classified according to pre-and postmenopausal subjects. ER (+) was seen in 61.4 per cent and ER (−) in 32.9 per cent before menopause, and ER (+) in 65.4 per cent and ER (−) in 30.8 per cent after menopause with no marked difference between the two. If classified according to histological type, ER (+) was seen in 73.2 per cent of those with papillotubular carcinoma and in 62.0 per cent of those with scirrhous carcinoma, whereas ER (−) was seen in 44.9 per cent of those with medullary tubular carcinoma. ER (+) was seen in carcinoma with apocrine metaplasia, lobular carcinoma and Paget's carcinoma. Concerning the relationship between primary tumors and metastatic lymph nodes, ER (+) for both was seen in 20 of 41 patients (48.8 per cent) whereas ER (−) for both was found in 9 of 41 patients (22.0 per cent). Four patients with local recurrences had a positive ER (+) at the beginning of treatment, but the ER became negative after hormonal treatment and chemotherapy. These data were presented at the 3rd EORTC, Amsterdam, April 27–29, 1983.     

Immunocytochemical study on the variation in estrogen receptors of primary and nodal metastases of breast cancer

The variation in estrogen receptors (ER) between primary and regional nodal metastatic lesions was examined by an estrogen receptor immunocytochemical assay (ER-ICA) in 25 mammary carcinoma patients. The ER status was evaluated in terms of the percentage of ER positive stained cells, staining intensity and distribution of those stained cells. The overall ER status was consistent in both sites, however, the percentage of ER positive cells and the staining intensity were not always consistent. A decrease in the percentage of ER positive cells and staining intensity was demonstrated in the nodal metastatic lesions of 4 and 3 cases out of a total 14 ER positive cases, respectively. The mean percentage of ER positive cells in the nodal metastatic lesions was 57 per cent compared with 73 per cent in primary lesions. Thus, a tendency of both the percentage of ER positive cells and the staining intensity to decrease in nodal metastases as when compared with primary lesions in breast cancer was demonstrated.     

Relationship between the content of estrogen and progesterone receptors and the pathological characteristics in human breast cancer

Assays of estrogen receptors (ER) and progesterone receptors (PgR) were performed by using the dextran-coated charcoal (DCC) method in 124 cases of invasive breast cancer. The results were correlated with clinical and pathological characteristics. There was no correlation between steroid hormone receptor contents and menopausal status, size of tumor, axillary lymph node status, or histological type. The presences of ER and PgR were significantly correlated with histological grade and its mitotic component. 78.3% of well-differentiated (Grade I) tumors were ER positive. Of this number, 61.1% were also PgR positive. In contrast, 69.0% of poorly differentiated (Grade III) tumors were ER and PgR negative. Tumors with a prominent lymphoid infiltration demonstrated a low frequency of positive ER and PgR. There was a significant inverse correlation between the degree of lymphoid infiltration and histological grade. These results suggest that the ER and PgR status of tumors may indicate a malignancy, and prognostic information can thus be obtained independently of other known factors such as size of the tumor and axillary lymph node status.     

青春期乳房肥大症乳腺组织中雌激素受体的表达

目的:探讨雌激素受体(ER)在青春期乳房肥大症乳腺组织中的表达及意义.方法:应用免疫组化SP法检测了18例青春期乳房肥大症及1 2例原发性小乳症乳腺组织中ER的表达情况.结果:ER在青春期乳房肥大症和原发性小乳症乳腺组织中的阳性表达率分别为88.89%和16.67%,两者比较差异有统计学意义(P＜0.01).结论:青春期乳房肥大症的发生可能与乳腺组织中ER的表达增加有关.     

雌激素受体在椎间盘组织中的表达及意义

【摘要】 目的：通过观察雌激素α、β受体在正常与退变的人椎间盘组织的表达,探讨雌激素受体（ER）与椎间盘退变的关系。方法：根据改良Pfirrmann分级将收集的椎间盘组织分为三组：对照组,外伤导致腰椎爆裂性骨折手术取出的正常髓核组织（Pfirrmann分级1~2级）;观察组,女性腰椎滑脱及腰椎间盘突出症手术取出的退变髓核组织,Pfirrmann分级3～4级为A组,5级为B组。用HE染色法观察对照组和A、B组各15例人腰椎椎间盘髓核组织及髓核细胞的形态学变化;用免疫组织化学染色法（Elivison二步法）检测对照组和A、B组髓核组织中ER-α、ER-β的表达;采用Western-blot法检测对照组和观察组髓核组织中ER-α、ER-β的表达。结果：HE染色示对照组髓核组织中髓核细胞分布均匀,形态完整,未见明显细胞凋亡现象,细胞外基质染色鲜亮,分布均匀;A、B两组髓核细胞分布不均匀,形态不规则,凋亡现象明显,细胞核增大,染色深,细胞外基质减少,色彩灰暗,B组较A组更为明显。免疫组织化学染色示ER-α、ER-β在对照组的髓核组织见有明显棕黄色颗粒,在A、B两组表达减少,以ER-β减少最显著,经统计学分析,A、B两组与对照组间ER-β的表达有显著性差异（P＜0.01）,ER-α的表达较对照组无统计学差异（P＞0.05）,其中A组和B组间无明显差异（P＞0.05）。Western-blot方法检测,ER-α表达A组（0.876±0.058）、B组（0.757±0.045）较对照组（0.885±0.036）降低,但无统计学差异（P>0.05）;ER-β表达A组（0.947±0.043）、B组（0.626±0.042）较对照组（1.275±0.150）显著降低（P＜0.01）,B组较A组表达明显减少（P＜0.01）。结论：在人的髓核组织中的髓核细胞（类软骨细胞）的胞核和胞浆中均存在ER。ER-α、ER-β在退变的椎间盘组织都明显减少,以ER-β最为明显,提示雌激素可能通过ER-β的介导对髓核细胞功能起调控作用。     

Estrogen and progesterone receptors in gallbladder cancer

Cancerous tissues from 21 patients with primary gallbladder cancer were examined immuno-histochemically for the presence of receptors for estrogen (ER) and progesterone (PGR). ER and PGR, localized in the nucleus, were evident in 52.4 per cent and 0 per cent of the patients, respectively. Furthermore, ER and PGR were positive only in the cytoplasm of cancer cells in 28.6 per cent and 66.7 per cent, respectively. There was a higher tendency of moderately- and poorly-differentiated adenocarcinoma to have an ER-positive rate than well-differentiated adenocarcinoma. With respect to the relationship between ER and sex, ER-positive nuclei were observed in 8 of 14 women (57.1 per cent) and 3 of 7 men (42.9 per cent), but the difference between the two was not significant due to the small number of subjects. These result suggested that gallbladder cancers with ER in the nuclei may respond to antihormone therapy.     

The expression of estrogen receptors in the tenosynovium of postmenopausal women with idiopathic carpal tunnel syndrome

The purpose of this study was to investigate estrogen receptor (ER) expression in tenosynovial tissues of postmenopausal woman with idiopathic carpal tunnel syndrome (CTS) to determine whether estrogen contributes to the pathogenesis of this condition. Biopsy samples of tenosynovial tissues were collected from 14 postmenopausal women (mean age; 57, range; 46–69 years) undergoing surgery for idiopathic CTS, and control specimens of tenosynovial tissue were collected from 6 postmenopausal women (mean age; 59, range; 48–68 years) without CTS. Histological and immunohistochemical examinations were performed to determine the distributions of ER‐α and ER‐β in tenosynovial tissues. Histological examinations showed a significant increase in fibroblast cell densities in the specimens from the carpal tunnel syndrome patients. ER‐α and ER‐β immunoreactivities were observed in fibroblasts and in the synovial lining cells of tenosynovial tissues, and these were significantly greater in patients than in controls. This study suggests that the up‐regulations of ERs in the tenosynovial tissue are associated with idiopathic CTS in postmenopausal women. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1469–1474, 2010     

米非司酮对人蜕膜中雌激素及孕酮受体的影响

本研究观察了服用米非司酮后人蜕膜中雌激素受体（ＥＲ）和孕酮受体（ＰＲ）的变化。６０名孕６～７周的妇女，被随机分为３组。在手术终止妊娠前的１２和２４小时两组中，分别一次性口服米非司酮２００ｍｇ，对照组服用安慰剂。服用米非司酮后，蜕膜中ＥＲ和ＰＲ的免疫组织化学染色反应与对照组比较增强了。卡方分析表明，服用米非司酮后，ＥＲ阳性标本的数量明显增加     

Analysis of estrogen receptor polymorphism in codon 325 by PCR-SSCP in breast cancer: association with lymph node metastasis

Breast cancer is the most frequent neoplasm in women. Expression of the estrogen receptor (ER) has a key role in breast cancer; the ER gene is located at chromosome 6q24-q27 and is made up of 8 exons with a total of 140 kb. The polymorphism in codon 325 of exon 4 (ER325) is a transition CCC→CCG. The objective of this study is to analyze the frequency of this polymorphism in breast cancer using the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) technology. DNA was extracted from tumor cells of 70 breast cancer patients and from the peripheral blood of 69 individuals without any known pathology (control group). Amplification products of the ER gene were analyzed by SSCP. In breast cancer patients the ER325 polymorphism was detected in 42.8% of the cases. In contrast, in the control group, the frequency of the same polymorphism was 24.6. Statistical comparison of the frequency distributions revealed that they are significantly different ( p = 0.023). There was also an association between ER325 polymorphism and the absence of lymph node metastases ( p = 0.038). Our data suggest that there is a relationship between the ER325 polymorphism and susceptibility to breast cancer (OR = 2.3; 1.10 < OR < 5.1) and that it can also be related with the metastasization process.     

The relationship of estrogen receptor status to DNA ploidy in breast cancer

The relationship of estrogen receptor(ER) status to DNA ploidy was investigated in 121 patients with breast cancer who underwent surgery. Lymph node status was evaluated histologically and ER levels were determined by the dextran-coated charcoal method, with a level of 3 fmol/mg·protein being considered positive. Flow cytometric DNA content was analyzed using paraffin-embedded tissue blocks. Sixty-three per cent of the specimens were ER+, while 37 per cent were negative. Sixty-one patients (50.4 per cent) were diploid and 60 aneuploid. A statistically significant correlation between the ER positivity rate and diploid DNA was found. Higher ER levels were seen in the postmenopausal patients with diploid tumors than in those with aneuploid tumors and there was a significant tendency for ER levels to be higher in the diploid tumors. Nodal status was not correlated with ER positivity or ploidy pattern. The present results indicate that ER levels are correlated with DNA ploidy, and reflect the degree of functional differentiation.     

Analysis of estrogen receptors in human breast cancer by assays using monoclonal antibodies and by the dextran-coated charcoal method

Estrogen receptors (ER) were analyzed in 63 human breast cancers by immunocytochemical assay, and by enzyme-immunoassay, using monoclonal antibodies against human ER protein, and also by the dextrancoated characoal method. The specific staining was observed only in the nucleus of cancer cells by the immunocytochemical assay, and the presence of nuclear staining by this assay was closely associated with the estimation of the cytosolic ER content by both the dextran-coated charcoal method and the enzyme-immunoassay. In the latter, the cytosolic ER content corres-pondingly increased with the nuclear ER content. Both the cytosolic and nuclear ER contents correlated well with those obtained by the dextrancoated charcoal method. Furthermore, the cytosolic ER contents obtained by the enzyme-immunoassay and the dextran-coated charcoal method correlated significantly with the age of the patient, but not with the nuclear ER contents. These above mentioned results suggest that ER is present mainly in the nucleus of breast cancer cells and that the cytosolic ER obtained by these two assays is the unoccupied one released from the nucleus.     

Interactions between estrogen and growth factor receptors in human breast cancers and the tumor-associated vasculature

Estrogens and growth factors stimulate the proliferation of human breast cancer cells by primary binding and activation of specific receptors that regulate downstream signaling events. Receptors for estrogen are phosphoproteins, and the biologic function of these proteins can be modulated by changes in their phosphorylation state. Signal transduction by growth factor receptors, including HER-2/neu and epidermal growth factor (EGF) receptors, can alter the phosphorylation of estrogen receptor (ER) and the biologic activity of ER-dependent signaling networks both in the presence and in the absence of estrogenic ligands. In addition, both estrogen and growth factor signaling pathways regulate the secretion of vascular endothelial growth factors that stimulate tumor-associated angiogenesis. These molecular interactions significantly impact breast cancer cell growth and survival, and integration of selected signal transduction inhibitors with antiestrogen therapies show promise as a new antitumor treatment strategy that will soon be evaluated in the clinic. Sensitive and reliable assays of estrogen, HER-2/neu, and EGF receptors and tumor-associated angiogenesis will be important biologic factors to consider in the choice of optimal antitumor therapies for patients with breast cancer.     

The discrepancy between immunocytochemical and biochemical assay of estrogen receptor in breast cancer patients treated by endocrine therapy

Estrogen receptor (ER) expression was investigated by ER-immunocytochemical assay (ICA) and the dextran coated charcoal (DCC) method in 10 recurrent or primary-advanced breast cancer patients treated with endocrine or chmmo-endocrine therapy. In 6 of these 10 patients, ER was examined both before and after treatments by the 2 methods. ER contents measured by the DCC method were found to be decreased after treatments, however, no change in the immunoreactivities of ER-ICA was observed. In the remaining 4 patients, the ER of new lesions refractory to endocrine or chemo-endocrine therapy was examined. ER status was determined as negative in 3 of the 4 patients by the DCC method, whereas by ER-ICA, the proportion of ER stained cells was about 70 per cent, those cells being diffusely distributed in the section. A discrepancy between ER-ICA and the DCC method was thus demonstrated in breast cancer patients treated by endocrine therapy.     

非小细胞肺癌患者血清雌激素水平与肺癌组织中雌激素受体表达及其临床病理意义

目的探讨非小细胞肺癌患者血清雌激素水平与肺癌组织中雌激素受体表达及其临床病理意义,为非小细胞肺癌的防治提供一些参考。方法选择2010年1月～2012年12月本院收治的经病理证实的肺腺癌患者36例作为观察组,同时选择同期在我院治疗的经病理学证实的肺鳞癌患者32例作为对照一组和来我院体检肺部健康的志愿者30例作为对照二组,然后利用免疫组织染色化学技术对所有参与实验的人员肺部组织进行瘦素、血清雌激素（E）及雌激素受体（ER）的检测,分别对观察组、对照一组、对照二组患者的瘦素、血清雌激素（E）及雌激素受体（ER）进行比较,然后对观察组男性肺腺癌患者和女性肺腺癌患者的瘦素、血清雌激素（E）及雌激素受体（ER）进行比较。结果观察组与对照一组、对照二组相比,瘦素、血清雌激素（E）及雌激素受体（ER）阳性表达明显高于其他两组,差异具有统计学意义（P〈0.05）;与男性相比较,观察组女性患者体内的瘦素、血清雌激素（E）阳性表达变化不显著（P〉0.05）,但是女性患者中ER阳性表达显著高于男性,差异有统计学意义（P〈0.05）。结论非小细胞肺癌患者的瘦素、血清雌激素（E）、雌激素受体（ER）的阳性表达高于正常人的,说明这三种因素可能参加着非小细胞肺癌的发生,可作为诊断非小细胞肺癌的重要依据。     

Effect of estrogen on the mixed lymphocyte reaction in normal individuals and prostatic cancer patients

Lack of initial response or relapse to hormones in advanced prostatic cancer may be due to an adverse effect of estrogen on host immune function. This study investigated the effect of dieth-ylstilbestrol diphosphate (DES-P) on the normal mixed lymphocyte reaction (MLR) and on the MLR in prostatic cancer patients before and during treatment with DES-P. These data showed that the normal MLR was suppressed by high concentrations of estrogen in vitro, but physiologic levels of DES-P were not suppressive. Therapeutic doses of DES-P did not suppress the spontaneous MLR of prostatic cancer patients compared with previous treatment. Estrogens did not significantly impair the immunologic responsiveness of normal individuals or prostatic cancer patients.