Pathologic changes in breast cancer after anti-estrogen therapy

Breast cancer patients do not commonly receive anti-estrogens prior to surgical excision. We reviewed a cohort of patients who received preoperative anti-estrogen therapy after baseline biopsy and then had a repeat biopsy after several weeks on treatment. Patients with estrogen receptor positive tumors received anastrozole and fulvestrant in combination with gefitinib. Core needle biopsies were performed at day 1 and 21, and tumors were completely excised if operable at day 112. All patients were postmenopausal. Following treatment, tumors had degenerative changes including smudged nuclei, decreased nuclear size, intranuclear vacuoles, vacuolated cytoplasm, and increased cellular discohesion. In addition, increased tubule formation and intracytoplasmic lumina were seen in 6/9 cases (66.7%) and decreased mitotic rate was demonstrated in 7/9 cases (77.8%). These findings indicate increased differentiation of the tumor cells in response to anti-estrogen therapy and that may correlate with clinical response.     

乳腺癌X射线征象与雌激素受体、孕激素受体和C-erbB-2表达相关性的研究进展

乳腺癌是女性最常见的恶性肿瘤之一,其发生、发展过程中大多伴随基因异常表达。雌激素受体（ER）、孕激素受体（PR）及C—erbB-2（即人表皮生长因子受体2）癌基因的表达情况是指导临床内分泌治疗及判断预后的主要参考指标。癌基因表达从不同角度反映了乳腺癌的恶性生物学行为,并引起组织病理学改变,进而形成多种影像学表现。因此,乳腺癌的X射线片表现可在一定程度上反映ER、PR和C-erbB-2的表达情况。乳腺X射线检查因诊断病变的准确率高、操作简单、价格低廉,仍是临床筛查及诊断乳腺癌的首选方法,并成为预测乳腺癌患者ER、PR和c—erbB-2表达情况的无创手段。在无条件做免疫组化的情况下,它对乳腺癌术前评估及非手术治疗发挥了重要作用,具有潜在的临床应用价值。该文主要对乳腺癌影像学表现与ER、PR和CIerbB-2表达的相关性研究进行综述。     

乳腺浸润性导管癌超声征象与雌激素受体表达的相关性初探

目的探讨二维超声预测乳腺浸润性导管癌雌激素受体表达水平的可能性。方法回顾性分析96例经手术病理证实的乳腺浸润性导管癌的二维超声征象,并与术后标本免疫组织化学染色的雌激素受体表达水平进行对比研究。结果本组雌激素受体阳性率为55.2%(53/96),具有毛刺征(蟹足征)、周边高回声晕、后方声衰减征象之一者,肿块雌激素受体阳性率显著高于不具有上述征象的肿块(P<0.01);无微钙化组雌激素受体阳性率比微钙化组略高,但差异无显著性意义(P>0.05)。结论乳腺浸润性导管癌二维超声征象可从一定程度上反映雌激素受体表达水平。     

Bisphenol A promotes X‐linked inhibitor of apoptosis protein‐dependent angiogenesis via G protein‐coupled estrogen receptor pathway

Bisphenol A (BPA), one of the high‐volume chemicals worldwide, has a core structure resembling that of natural estradiol. Recent evidence has demonstrated that exposure to BPA has a relationship with the risk of cancer. The objective of our study is to investigate the mechanisms underlying the pro‐angiogenic effects of BPA. We demonstrated that BPA markedly induces endothelial cell proliferation, migration and tube formation by activating endothelial nitric oxide synthase. BPA‐induced nitric oxide generation appeared to be associated with the X‐linked inhibitor of apoptosis protein (XIAP), which competes with endothelial nitric oxide synthase for caveolin‐1. BPA was shown to exert its pro‐angiogenic effect by upregulating XIAP expression via G protein‐coupled estrogen receptor (ER) activation but not via ERα or ERβ. Our data suggest that 100 nM BPA promote angiogenesis in a G protein‐coupled ER‐dependent genomic pathway, and provide a novel insight into the potential role of XIAP in mediating the pro‐angiogenic effects of BPA in endothelial cells. Copyright © 2015 John Wiley & Sons, Ltd.     

Hazard identification of cis/trans-zearalenone through the looking-glass

Among the food-related health issues, the presence of contaminants has a prominent role, due to the wide range of exogenous compounds that can occur in food commodities and to their large differences in structure and biological activity. A comprehensive assessment of the related risk is thus actually demanding in terms of time and facilities involved. In this context, the use of computational strategies can be an effective choice for supporting the hazard identification procedure at the early stage. In this work, we focused on the food contaminant zearalenone by comparing the trans and cis isomers, respectively the well-known mycoestrogen and its still largely understudied isomer. We estimated the possible effects exerted by human metabolism on the xenoestrogenicity of cis-ZEN by using a validated in silico strategy based on docking simulations and rescoring procedures. Similarly, the exploitation of the most promising enzymatic detoxifying routes designed for trans-ZEN – which relies on the enzyme lactono hydrolase from Clonostachys rosea – has been assessed for the cis-isomer as well. Our results showed that both isomers can act as functional analogues with respect to xenoestrogenic activity, and several cis-ZEN metabolites with high biological potential have been identified. On the contrary, in spite of the high degree of structural analogy, the cis isomer showed a pattern of interaction with the degrading enzyme in stark contrast with that observed for trans-ZEN. For these reasons, the outcomes presented herein strongly support the inclusion of cis-ZEN in further studies of occurrence, metabolism and bioactivity assessment, and suggest the need for a dedicated handling for the cis isomer in risk assessment studies.     

ER、PR的表达与乳腺癌患者化疗相关认知障碍的相关性研究

目的：探讨雌激素受体( ER)和孕激素受体( PR)与乳腺癌患者化疗相关认知障碍( CICI)的相关性。方法60例术后辅助化疗后乳腺癌患者作为乳腺癌组,其中 ER 和PR双阴性患者30例为A组、ER和PR双阳性患者30例为B组;另以年龄及教育程度相匹配的60例健康女性志愿者为对照组。分别对其进行简易精神状态量表( MMSE)和中文听觉词语学习测验( AVLT)测查。结果乳腺癌组与对照组MMSE成绩相比差异有统计学意义( t =-12．824, P <0．05);A组和B组在MMSE、即刻记忆和延迟记忆成绩方面差异均有统计学意义( t=-3．311、-3．616、-2．264, P<0．05)。结论化疗后乳腺癌患者存在不同程度的认知功能障碍,且ER和PR双阴性患者在总体认知功能及记忆方面损害较ER和PR双阳性患者显著( P<0．05),提示ER、PR的不同表达可能与乳腺癌CICI的异质性有关。     

盐酸帕罗西汀对卵巢切除大鼠学习记忆能力及血清雌激素水平的影响

目的：探讨抗抑郁剂盐酸帕罗西汀对卵巢切除大鼠学习记忆能力、血清雌激素水平及大鼠海马雌激素受体表达的影响。方法采用 SD 雌鼠双侧卵巢切除（OVX）作为雌激素波动引起的抑郁与认知障碍模型,用 Morris 水迷宫实验来测试大鼠的学习记忆功能。实验共分为正常对照组、OVX对照组、OVX 药物组。予5-羟色胺重摄取抑制剂类药物：盐酸帕罗西汀10 mg／（kg·d）干预4周。采用 ELISA 法测量SD 大鼠血清黄体生成素、卵泡刺激素、雌激素。免疫组化法检测大鼠海马雌激素受体α（ERα）和雌激素受体β（ERβ）的阳性细胞表达数。结果① Morris 水迷宫实验中,OVX对照组和 OVX 药物组的逃避潜伏期明显缩短,停留在平台时间百分比明显增加。② OVX 药物组的血清雌激素较OVX 对照组明显增加（P ＜0．05）。③药物组与非药物组的ERα、ERβ表达无明显差异。结论帕罗西汀增加OVX 大鼠血清雌激素水平和改善学习记忆能力,而对海马ERα、ERβ表达无明显影响。     

Contribution of estrogen receptor subtypes,ERα, ERβ, and GPER1 in rapid estradiol‐mediated enhancement of hippocampal synaptic transmission in mice

Estradiol rapidly modulates hippocampal synaptic plasticity and synaptic transmission; however, the contribution of the various estrogen receptors to rapid changes in synaptic function is unclear. This study examined the effect of estrogen receptor selective agonists on hippocampal synaptic transmission in slices obtained from 3–5‐month‐old wild type (WT), estrogen receptor alpha (ERαKO), and beta (ERβKO) knockout female ovariectomized mice. Hippocampal slices were prepared 10–16 days following ovariectomy and extracellular excitatory postsynaptic field potentials were recorded from CA3‐CA1 synaptic contacts before and following application of 17β‐estradiol‐3‐benzoate (EB, 100 pM), the G‐protein estrogen receptor 1 (GPER1) agonist G1 (100 nM), the ERα selective agonist propyl pyrazole triol (PPT, 100 nM), or the ERβ selective agonist diarylpropionitrile (DPN, 1 µM). Across all groups, EB and G1 increased the synaptic response to a similar extent. Furthermore, prior G1 application occluded the EB‐mediated enhancement of the synaptic response and the GPER1 antagonist, G15 (100 nM), inhibited the enhancement of the synaptic response induced by EB application. We confirmed that the ERα and ERβ selective agonists (PPT and DPN) had effects on synaptic responses specific to animals that expressed the relevant receptor; however, PPT and DPN produced only a small increase in synaptic transmission relative to EB or the GPER1 agonist. We demonstrate that the increase in synaptic transmission is blocked by inhibition of extracellular signal‐regulated kinase (ERK) activity. Furthermore, EB was able to increase ERK activity regardless of genotype. These results suggest that ERK activation and enhancement of synaptic transmission by EB involves multiple estrogen receptor subtypes. © 2015 Wiley Periodicals, Inc.     

Who will benefit from treatment with selective estrogen receptor modulators (SERMs)?

Clinical trials have demonstrated that the selective estrogen receptor modulator raloxifene can reduce the risk of vertebral fracture, but have not unequivocally demonstrated an effect on non-vertebral fracture. Consequently it is recommended that raloxifene be used mainly in postmenopausal women with milder osteoporosis as a preventive measure or for treatment in those with predominantly spinal osteoporosis. Since the effects of raloxifene on bone mineral density and bone turnover may reverse soon after cessation, it is recommended that raloxifene be used as long-term therapy for 5-10 years. Because of its quicker offset, use of raloxifene may have advantages over potent bisphosphonates if use of anabolic agents are contemplated in an individual patient.