雌激素受体α对实验性自身免疫性脑脊髓炎小鼠TIMP-1及TIMP-2表达的影响

目的 以实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)作为多发性硬化(multiple sclerosis,MS)的动物模型,初步探讨雌激素和雌激素受体α(estrogen receptor α,Erα)在EAE中的抗炎作用及其作用机制.方法 在小鼠侧脑室立体定位注射Erα重组慢病毒,鉴定Erα重组慢病毒在体感染中枢神经系统(central nervous system,CNS)的最佳剂量.将雌二醇及Erα重组慢病毒干预EAE小鼠与对照组比较,观察 各组小鼠的临床症状及体重的变化,通过H&E染色及Luxol fast blue-H&E染色对比各组炎症反应及脱髓鞘情况,以实时荧光定量PCR及Western blot方法检测金属蛋白酶组织抑制因子-1(tissue-inhibitors of matrix metalloproteinase-1,TIMP-1)及TIMP-2.结果 15μl Erα重组慢病毒能感染小鼠CNS.与对照组相比,雌二醇及过表达Erα可以降低EAE小鼠的发病率、体重丢失及临床症状,减轻脑和脊髓中炎性细胞浸润和神经纤维的髓鞘脱失,在发病急性期增加TIMP-1及TIMP-2,减轻在缓解期TIMP-1、TIMP-2的病理性表达增高.结论 雌激素及Erα可以抑制EAE的炎症反应,该作用机制可能是通过增加EAE小鼠急性发病期脑组织中TIMP-1及TIMP-2实现的.     

Overexpression of c-Myc and Bcl-2 during progression and distant metastasis of hormone-treated breast cancer

The aim of this study was to identify molecules involved in the proliferation and survival of recurrent estrogen receptor (ER)-positive breast cancer at the site of metastasis. Most studies of biomarkers are done using the initial primary breast tumor whereas pathological studies of breast cancer lesions after distant recurrence are scarce. Here we evaluated the expression of the oncogenes c-Myc and Bcl-2, mediators of estrogen-dependent proliferation and survival, during breast cancer progression and relapse after adjuvant hormonal therapy. Using a preclinical model of tamoxifen-resistant growth, we found overexpression of c-Myc in all (3/3) and of Bcl-2 in most (2/3) tamoxifen resistant-breast cancer variants. To determine whether c-Myc and Bcl-2 are expressed during breast cancer progression in the clinics we identified breast cancer patients who had received adjuvant hormonal therapy for the treatment of their localized disease and had later experienced relapse. From 583 patients who had received adjuvant hormonal therapy a total of 82 experienced recurrence. Nevertheless, only 22 patients had had a biopsy of their metastatic lesion done after relapse. Twenty-one biopsies were useful for this biomarker study. These biopsies were obtained mostly (20) from breast cancer patients who had received tamoxifen as their adjuvant hormonal therapy. One patient had received an aromatase inhibitor instead. Our results showed that almost all (20) metastatic recurrences expressed ER. Expression of c-Myc was observed in 18 out of 19 metastatic lesions scored while expression of Bcl-2 was detected in 17 out of 21 metastatic tumors. A correlation between ER expression and Bcl-2, but not with c-Myc, was found in these recurrent metastatic lesions. In addition, c-Myc expression was correlated with the nuclear grade of the metastatic lesion. Thus, the frequent expression of c-Myc and Bcl-2 in metastatic breast cancer recurrences suggests that combining hormonal therapy with strategies to block c-Myc and Bcl-2 may prevent growth of ER-positive breast cancer at the site of metastasis.     

Facial symmetry detection ability changes across the menstrual cycle

The effects of menstrual cycle phase and hormones on women's visual ability to detect symmetry and visual preference for symmetry were examined. Participants completed tests of symmetry detection and preference for male facial symmetry at two of three menstrual cycle phases (menses, periovulatory, and luteal). Women were better at detecting facial symmetry during the menses than luteal phase of their cycle. A trend indicated the opposite pattern for dot symmetry detection. Similarly, change in salivary progesterone levels across the cycle was negatively related to change in facial symmetry detection scores. However, there was no clear evidence of a greater preference for facial symmetry at any cycle phase, despite an overall preference for facial symmetry across phases. These findings suggest a menses phase advantage and a low progesterone advantage in women's ability to detect facial symmetry. The results are discussed in the context of hormonal, evolutionary mate selection, and functional neurocognitive theories.     

Influence of estrogens and antiestrogens on the expression of selected hormone-responsive genes

Estrogen exerts a primary regulatory role on a wide variety of physiological processes in different tissues and organs. Agonistic ad antagonistic compounds are widely used in human health and, therefore, a deep understanding of their mechanisms of action at the molecular level is mandatory. The effect of 17beta-estradiol and three antiestrogenic drugs, comprising two selective estrogen receptor modulator (SERM, 4-OH-tamoxifen, Raloxifene) and the pure antiestrogen ICI 182,780, on genome-wide gene expression levels was evaluated in breast carcinoma cell lines by DNA microarray analysis. Different clusters of genes, showing specific coregulation patterns, were found. First, several groups of genes displaying temporal-specific up- or down-regulation were characterized. Second, clusters of genes responding to different antiestrogenic drugs in either antagonstic or agonistic fashion, were found. Genes responding specifically to antiestrogens, but not to estrogen, were also identified. In addition, each individual compound exhibited a very specific gene regulation. Bioinformatic analysis was applied to the regulatory sequences of different groups of genes and confirmed that specific pathways and secondary responses are activated at each temporal point and in response to different compounds. Our results underline the complexity of genomic responses to estrogen in breast cancer cells and strongly suggest that the molecular characterization of estrogen agonists and antagonists used in human therapy should be carefully studied.     

子宫内膜异位症患者异位内膜间质细胞雌激素受体-a、雌激素受体-β的表达

目的：观察雌激素受体-α（ER-α）和雌激素受体-β（ER-β）在子宫内膜异位症患者在位及异位内膜间质细胞中的表达，探讨其与子宫内膜异位症发生机制的关系。方法：应用体外细胞培养，流式细胞术检测等方法，检测子宫内膜异住症患者在位及异住内膜间质细胞中ER—α和ER—β的表达。结果：子宫内膜异住症患者ER-α及ER-β在异位内膜间质细胞中的含量均低于在位内膜和子宫肌瘤患者在位内膜，但两组受体间均无明显差异。结论：子宫内膜异住症患者在位内膜和异位内膜间质细胞中ER—α和ER—β表达有明显差异，表明除了已知的ER—α对子宫内膜增殖和分化有作用外，ER-β可能对子宫内膜的功能也有重要影响，并提示深入研究二者之间的关系对子宫内膜异位症的发生发展、临床生物特性、治疗及预后有重要价值     

The effects of Vigna unguiculata on cardiac oxidative stress and aorta estrogen receptor-β expression of ovariectomized rats

ObjectiveTo investigate whether Vigna unguiculata (V. Unguiculata, VU) able to reduced oxidative stress in cardiac and modulate the aorta estrogen receptor-β of ovariectomized rats.MethodsThirty female Wistar rats were divided into 5 groups (n=6); control (sham) group; ovariectomy group (OVX); OVX + VU₁ (0.5 mg/kg); OVX + VU₂ (2.5 mg/kg); and OVX + VU₃ (5 mg/kg). The administration VU was started 28 days after surgery following 30 days later. Cardiac malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured colorimetrically. Estrogen receptor-β in the aorta was analyzed immunohistochemically.ResultsLevel of MDA was significantly higher in the OVX group compared to the control group (P< 0.05), but the level of SOD was significantly lower. The level of MDA was significantly lower in OVX + VU compared with OVX group (P<0.05), to reach the level at a control group in OVX + VU₂. Administration of VU significantly increases the level of SOD compared with OVX group (P<0.05), to reach the level at a control group in third dose of VU (P>0.05). The level of estrogen receptor-β was significantly decreased in the OVX group compared to the control group (P<0.05). OVX + VU₃ could significantly increase the level of estrogen receptor-β compared to OVX group (P<0.05), to reach a level in the control group (P>0.05).ConclusionsV. unguiculata is an alternative therapy in decreasing cardiac oxidative stress in ovariectomized rats. Besides, high dose of V. unguiculata also able to increase aorta estrogen receptor-β expression in ovariectomized rats.     

p53 inactivation decreases dependence on estrogen/ERK signalling for proliferation but promotes EMT and susceptility to 3-bromopyruvate in ERα breast cancer MCF-7 cells

Background

Most breast cancers express the estrogen receptor alpha (ERα⁺), harbor wt TP53, depend on estrogen/ERK signalling for proliferation, and respond to anti-estrogens. However, concomittant activation of the epidermal growth factor receptor (EGFR)/MEK pathway promotes resistance by decreasing estrogen dependence. Previously, we showed that retroviral transduction of mutant p53 R175H into wt TP53 ERα⁺ MCF-7 cells induces epidermal growth factor (EGF)-independent proliferation, activation of the EGF receptor (p-EGFR) and some characteristics of epithelial-mesenchymal transition (EMT).

Purpose

To investigate whether p53 inactivation augments ERα⁺ cell proliferation in response to restrictive estradiol, chemical MEK inhibition or metabolic inhibitors.

Results

Introduction of mutant p53 R175H lowered expression of p53-dependent PUMA and p21WAF1, decreased E-cadherin and cytokeratin 18 associated with EMT, but increased the % of proliferating ERα⁺/Ki67 cells, diminishing estrogen dependence. These cells also exhibited higher proliferation in the presence of MEK-inhibitor UO126, reciprocally correlating with preferential susceptibility to the pyruvate analog 3-bromopyruvate (3-BrPA) without a comparable response to 2-deoxyglucose. p53 siRNA silencing by electroporation in wt TP53 MCF-7 cells also decreased estrogen dependence and response to MEK inhibition, while also conferring susceptibility to 3-BrPA.

Conclusions

(a) ERα⁺ breast cancer cells dysfunctional for TP53 which proliferate irrespective of low estrogen and chemical MEK inhibition are likely to increase metabolic consumption becoming increasingly susceptible to 3-BrPA; (b) targeting the pyruvate pathway may improve response to endocrine therapy in ERα⁺ breast cancer with p53 dysfunction.     

Expression and clinical implications of estrogen receptors in thoracic malignancies: a narrative review

Thoracic malignancies represent a significant global health burden with incidence and mortality increasing year by year. Thoracic cancer prognosis and treatment options depend on several factors, including the type and size of the tumor, its location, and the overall health status of patients. Gender represents an important prognostic variable in thoracic malignancies. One of the greatest biological differences between women and men is the presence of female sex hormones, and an increasing number of studies suggest that estrogens may play either a causative or a protective role in thoracic malignancies. Over the past 60 years since the discovery of the first nuclear estrogen receptor (ER) isoform α and the almost 20 years since the discovery of the second estrogen receptor, ERβ, different mechanisms governing estrogen action have been identified and characterized. This literature review reports the published data regarding the expression and function of ERs in different thoracic malignancies and discuss sex disparity in clinical outcomes. From this analysis emerges that further efforts are warranted to better elucidate the role of sex hormones in thoracic malignancies, and to reduce disparities in care between genders. Understanding the mechanisms by which gender-related differences can affect and interfere with the onset and evolution of thoracic malignancies and impact on response to therapies could help to improve the knowledge needed to develop increasingly personalized and targeted treatments.