miR-181a表达水平与ER阳性乳腺癌对内分泌治疗敏感性的关系

目的:研究miR-181a表达水平与雌激素受体（estrogen receptor,ER）阳性乳腺癌对内分泌治疗敏感性之间的关系。方法:采用梯度递增法诱导乳腺癌他莫昔芬耐药细胞株,利用集落形成实验检测细胞对他莫昔芬的敏感性。利用RT-PCR法检测miR-181a表达的情况,利用KM-plotter分析miR-181表达与乳腺癌患者预后之间的关系。结果:我们成功的诱导了MCF-7他莫昔芬继发耐药细胞株TAM-R。RT-PCR分析结果显示:他莫昔芬继发耐药的TAM-R细胞株及原发他莫昔芬耐药BT474细胞株中miR-181a的表达水平均显著高于对他莫昔芬敏感的MCF-7细胞株。生存分析结果显示:miR-181a的表达水平与ER阴性乳腺癌患者的总生存无关,但在ER阳性乳腺癌中miR-181a表达高的患者总生存明显差于miR-181a低表达者。进一步分析结果显示:在ER阳性但未接受内分泌治疗的乳腺癌患者中miR-181a表达与总生存无关,但在ER阳性且接受过内分泌治疗的乳腺癌患者中miR-181a高表达者总生存显著差于miR-181a低表达者。结论:miR-181a高表达ER阳性乳腺癌患者对内分泌治疗敏感性差,miR-181a可能是预测ER 阳性乳腺癌对内分泌治疗敏感性的指标。     

乳腺癌中ERα及ERβ的表达与C-erbB-2表达关系的研究

 目的 研究ERα阳性表达的乳腺癌组织中ERβ蛋白的表达与C-erbB-2蛋白表达情况，探讨ERβ亚型表达的变化与内分泌治疗抵抗之间的关系，为乳腺癌临床内分泌治疗方案的确定提供更确切的理论依据。方法 对83例乳腺癌患者，用免疫组化法检测组织中ERα的表达，同时检测ERα阳性组织中原癌蛋白C-erbB-2及ERβ表达的变化。结果 48例ERα阳性的乳癌组织中，C-erbB-2表达阳性的乳腺癌中，ERβ的表达量显著升高（P＜0.001）。结论 ERβ高表达与内分泌治疗的耐药表现有关，检测ERβ的表达水平可作为另一预测内分泌治疗效果的有用指标。     

FGFR1蛋白在ER阳性乳腺癌中的表达情况及其与ER、预后的相关性

目的 探讨成纤维细胞生长因子受体1(FGFR1)蛋白在雌激素受体(ER)阳性乳腺癌中的表达水平及与ER、预后的关系。方法 回顾性分析89例ER阳性乳腺癌患者临床资料。所有患者均行手术治疗,术后及时送检肿瘤标本,经免疫组织化学法检测FGFR1蛋白表达情况。统计FGFR1蛋白表达在ER阳性乳腺癌中的表达水平,分析不同FGFR1表达患者临床病理特征差异;比较不同FGFR1蛋白表达患者生存率差异。结果 89例ER阳性乳腺癌患者体内均存在FGFR1蛋白表达,其中高表达58例,低表达31例;高、低表达组肿瘤分期、肿瘤大小、淋巴结转移、ER表达相比,差异有统计学意义(P<0.05)。随访3年,89例ER阳性患者存活71例,存活率为79.78(71/89);FGFR1蛋白低表达组存活率为93.55%(29/31),高于FGFR1蛋白高表达组72.41%(42/58),差异有统计学意义(χ²=5.593,P=0.018)。结论 FGFR1蛋白在ER阳性乳腺癌中存在不同程度表达,且FGFR1蛋白高表达患者ER表达水平偏低,并可对患者预后造成影响。     

E R阳性乳腺癌中FGFR1蛋白的表达与ER及预后的关系

背景与目的：乳腺癌是严重危害女性健康的常见恶性肿瘤之一，内分泌治疗是乳腺癌综合治疗中的重要措施之一。约30%激素敏感型乳腺癌患者并不能从内分泌治疗中获益。成纤维细胞生长因子受体1（fibroblast growth factor receptors 1，FGFR1）的表达与雌激素受体（estrogen receptor，ER）阳性乳腺癌患者内分泌治疗耐药可能有关。该研究旨在探讨ER阳性乳腺癌中FGFR1蛋白的表达水平对乳腺癌临床病理学特征及预后的影响。方法：选取哈尔滨医科大学附属肿瘤医院2008年9月-2011年12月收治的184例ER阳性乳腺癌患者，通过免疫组织化学方法检测FGFR1蛋白的表达；采用χ²检验评估FGFR1蛋白水平与乳腺癌临床病理学特征的关系；采用Spearman相关分析评估变量间是否存在相关性；运用COX回归及Kaplan-Meier法分析FGFR1表达水平对乳腺癌预后的影响。结果：在ER阳性乳腺癌中，FGFR1高表达的患者更易发生区域淋巴结转移（P=0.012，r=0.186），且FGFR1的表达水平与ER的表达水平之间存在显著的负相关关系（P=0.011，r=-0.221）。COX单因素分析显示，TNM分期、区域淋巴结转移情况、Ki-67阳性率及FGFR1表达情况与ER阳性乳腺癌预后有关；进一步进行多因素分析发现，淋巴结转移情况（OR=1.744，95%CI：1.002~3.034，P=0.049）和Ki-67阳性率（OR=1.882，95%CI：1.015~3.491，P=0.045）是ER阳性乳腺癌的独立风险因素。Kaplan-Meier生存分析提示，FGFR1高表达患者预后不良（P=0.036）。结论：在ER阳性乳腺癌中，FGFR1蛋白水平与患者ER的表达水平呈显著负相关，且FGFR1高表达提示患者预后不良。     

HER—2过表达与乳腺癌内分泌治疗临床疗效的关系

内分泌耐药在乳腺癌治疗中是一个严峻的临床问题，其耐药的机制非常复杂且涉及多种基因的参与和调控。研究表明，在乳腺癌中HER—2的表达与雌激素受体取呈负相关，但HER—2过表达的乳腺癌患者中仍有将近一半ER为阳性。现综述HER-2过表达、ER阳性乳腺癌患者内分泌治疗的疗效。     

ER阳性乳腺癌中MUC1的强阳性表达及其与预后的关系

背景与目的:黏蛋白1(mucin 1,MUC1)主要作为血清学分子标记应用于乳腺癌患者术后肿瘤复发转移的监测,但其在乳腺癌患者术后早期检测对预后的价值尚不明确.本研究旨在通过检测乳腺癌组织中MUC1的强阳性表达,分析其与ER表达以及预后的关系,以探讨MUC1强阳性表达在乳腺癌术后早期检测对预后的作用.方法:采用免疫组织化学法检测134例乳腺癌组织中MUC1的强阳性表达情况,并分析其与ER表达以及预后的关系.结果:本组乳腺癌组织中MUC1强阳性表达率为47.0%,乳腺癌组织中MUC1强阳性表达与ER阳性表达存在着显著的正相关关系(x2=10.09,P＜0.01,r=0.27).在ER阴性乳腺癌患者中尚不能认为MUC1强阳性表达与预后相关(P=0.26);经单因素和多因素分析,在ER阳性并接受他莫昔芬治疗的乳腺癌患者中,MUC1强阳性表达、Her-2强阳性表达和淋巴结转移状态均是独立的预后因子(P＜0.05).同时,多因素分析表明Her-2强阳性表达的优势比最大(OR=12.41),淋巴结转移状态次之,MUC1强阳性表达最小.结论:在乳腺癌组织中MUC1强阳性表达与ER表达正相关,在ER阳性并接受他莫昔芬治疗的乳腺癌患者中MUC1强阳性表达具有独立的预后价值.     

ER、PR在乳腺癌中的表达及临床意义

目的：检测并分析ER和PR在乳腺癌中的表达,探讨ER、PR在内分泌治疗中的作用。方法：选取137例有完整临床和病理资料的乳腺癌患者,采用免疫组化法检测其乳腺癌组织中的ER、PR表达。结果：ER,PR阳性率分别为55．47％,51．09％,PR（＋）患者,其ER大多数表达阳性;绝经后ER阳性患者较绝经前患者多;ER、PR阳性率表达与淋巴结是否转移无明显相关性。结论：ER和PR在乳腺癌组织中的存在可以预测肿瘤对激素治疗是否敏感,为临床指导辅助内分泌治疗提供有力的证据。     

HER-2过表达与乳腺癌内分泌治疗临床疗效的关系

内分泌耐药在乳腺癌治疗中是一个严峻的临床问题,其耐药的机制非常复杂且涉及多种基因的参与和调控.研究表明,在乳腺癌中HER-2的表达与雌激素受体ER呈负相关,但HER-2过表达的乳腺癌患者中仍有将近一半ER为阳性.现综述HER-2过表达、ER阳性乳腺癌患者内分泌治疗的疗效.     

ER、PR在乳腺癌中的表达及临床意义

目的:检测并分析ER和PR在乳腺癌中的表达,探讨ER、PR在内分泌治疗中的作用. 方法: 选取137例有完整临床和病理资料的乳腺癌患者,采用免疫组化法检测其乳腺癌组织中的ER、PR表达 . 结果:ER,PR阳性率分别为55.47%,51.09%,PR(+)患者,其ER大多数表达阳性;绝经后ER阳性患者较绝经前患者多;ER、PR阳性率表达与淋巴结是否转移无明显相关性.结论: ER和PR在乳腺癌组织中的存在可以预测肿瘤对激素治疗是否敏感,为临床指导辅助内分泌治疗提供有力的证据.     

1336例乳腺癌组织中ER、PR的表达及临床意义

目的研究1336例乳腺癌手术病例标本中ER、PR表达与乳腺癌生物学行为的关系.方法用免疫组化S-P法检测1336例乳腺癌手术标本中ER、PR的表达.结果1336例乳腺癌中ER阳性表达788例,PR表达1020例,共同阳性表达658例(49.3%);ER、PR表达与乳腺癌肿瘤大小及发病年龄无关;ER、PR阳性表达与乳腺癌TNM分期有关P＜0.05;此外ER表达与乳腺癌病理学分类及腋淋巴结转移呈负相关P＜0.05.结论ER、PR参与了乳腺癌生物学行为的调控,检测ER、PR的表达情况有助于乳腺癌患者的预后评估,并且为内分泌治疗提供依据.     

Expression of estrogen receptor beta and phosphorylation of estrogen receptor alpha serine 167 correlate with progression-free survival in patients with metastatic breast cancer treated with aromatase inhibitors

Aromatase inhibitor (AI) is widely used as an endocrine treatment in postmenopausal patients with hormone receptor-positive breast cancer. To identify useful prognostic factors for patients with metastatic breast cancer treated with AI therapy, we investigated the association between several hormone receptor-related factors and prognosis. The expressions of estrogen receptor-α (ERα), ERβ, progesterone receptor, the phosphorylation of ERα serine 118 (Ser118) and ERα Ser167 were examined using immunohistochemical techniques for the primary tumors of 41 patients with metastatic breast cancer who received first-line AI therapy after relapse. To assess the associations of protein expression and phosphorylation levels with progression-free survival (PFS), the levels of each factor were categorized into low and high values at optimal cutoff points. In univariate analysis, high ERα expression and high ERα Ser167 phosphorylation correlated with longer PFS (p = 0.016 and 0.013, respectively). In multivariate analysis, low ERβ expression and high ERα Ser167 phosphorylation correlated with longer PFS (p = 0.031 and 0.004, respectively). Patients with both low ERβ expression and high ERα Ser167 phosphorylation had longer PFS than the others (p = 0.0107). These data suggest that the expression of ERβ and phosphorylation of ERα Ser167 may be useful prognostic factors in patients with metastatic breast cancer who received first-line AI therapy.     

Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays

With the goal of identifying key factors involved in human breast cancer progression, we applied human cytokine antibody arrays we have developed to screen cytokine expression levels in human breast cancer cell lines and identified interleukin (IL)-8 as a key factor involved in breast cancer invasion and angiogenesis. Elevated expression of IL-8 in breast cancer cells was associated with breast cancer invasiveness and angiogenesis. Neutralization of antibody against IL-8 specifically blocked IL-8-mediated tumor cell invasion and angiogenesis. Furthermore, IL-8 levels in human breast cancer cells were closely related to estrogen receptor (ER) status. ER positive cells expressed low levels of IL-8 whereas ER negative cells expressed high levels of IL-8. Expression of exogenous ERalpha substantially inhibited IL-8 expression. Our findings raise intriguing questions regarding the role of IL-8 in the development and progression of human breast cancer in association with ER status.     

ER阴性乳腺癌高表达乳腺癌干细胞标志物乙醛脱氢酶1

目的探讨85例乳腺浸润性导管癌中肿瘤干细胞标志物乙醛脱氢酶1(ALDH1)的表达情况及与临床病理特征的关系。方法采用免疫组化法检测乳腺组织芯片85例乳腺浸润性导管癌组织中ALDH1的表达并分析其临床意义。结果 ALDH1在雌激素受体(ER)阴性的乳腺癌中表达率(34.6%)显著高于ER阳性者(12.1%;P=0.024)。不同亚型乳腺癌中存在ALDH1表达的显著差异,其中三阴性乳腺癌中ALDH1的表达较高(50.0%,P=0.034)。ALDH1的表达在不同大小肿块的肿瘤中也存在差异,其中肿块小于2 cm的乳腺癌中ALDH1的表达率最高(50.0%;P=0.040)。而ALDH1的表达与患者年龄、肿瘤分级、淋巴结转移、疾病分期及PR、HER-2状态无关(P>0.05)。结论 ER阴性乳腺癌尤其是三阴性乳腺癌中ALDH1的表达率较高,提示ER阴性乳腺癌中存在较高比例的干细胞,进而有助于更好地理解其预后差的特点。     

Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer

Toll-like receptor-9 (TLR9) is a DNA receptor widely expressed in cancers. Although synthetic TLR9 ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with significantly shortened disease-specific survival in patients with triple negative but not with ER+ breast cancers. A likely mechanism of this clinical finding involves differential responses to hypoxia. Our pre-clinical studies indicate that while TLR9 expression is hypoxia-regulated, low TLR9 expression has different effects on triple negative and ER+ breast cancer invasion in hypoxia. Hypoxia-induced invasion is augmented by TLR9 siRNA in triple negative, but not in ER+ breast cancer cells. This is possibly due to differential TLR9-regulated TIMP-3 expression, which remains detectable in ER+ cells but disappears from triple-negative TLR9 siRNA cells in hypoxia. Our results demonstrate a novel role for this innate immunity receptor in cancer biology and suggest that TLR9 expression may be a novel marker for triple-negative breast cancer patients who are at a high risk of relapse. Furthermore, these results suggest that interventions or events, which induce hypoxia or down-regulate TLR9 expression in triple-negative breast cancer cells may actually induce their spread.     

Significance of estrogen receptor subtypes in breast tumorigenesis and progression

The aim of the study was to investigate the effects of estrogen receptor (ER) subtypes (ERα and ERβ) on breast cancer development and progression. The expression level of ERα and ERβ in breast cancer tissues and paired normal breast tissues were detected by Western blot analysis and immunohistochemistry (IHC) staining. The features of ERα and ERβ status in cancer tissues or normal breast tissues and the correlations between clinicopathological characteristics and prognosis were analyzed. The expression levels of ERα and ERβ in breast cancer tissues are significantly lower than those in the paired normal tissues. The expression of ERβ is decreased more than that of ERα. ERα expression levels in cancer tissues are associated with tumor diameter, tumor–node–metastasis (TNM) stage, and progesterone receptor (PR) status. However, ERβ expression levels in cancer tissues are not correlated with clinicopathological factors of patients with breast cancer. In conclusion, ER subtypes might play different roles in the development of breast cancer.     

细胞周期相关因子与乳腺细胞的癌变及生物学特性的相关性研究

目的：研究正常乳腺上皮细胞与乳腺癌细胞之间以及不同恶性程度的乳腺癌细胞之间的细胞周期相关因子的表达异同。方法：采用Western印迹法检测正常乳腺细胞株AG11132A、ER阳性和乳腺癌细胞株MCF－7及ER阴性的乳腺癌细胞株MDA－MB－231之间细胞周期蛋白D1、E及P21蛋白表达的异同及与其生物学特性的关系。结果：（1）正常乳腺上皮细胞株高表达P21蛋白,低表达周期蛋白E。与正常细胞相比,乳腺癌细胞株MCF－7、MDA－MB－231细胞高表达周期蛋白E,其中表达的周期蛋白E中存在异常的你分子量周期蛋白E成分,而正常乳腺上皮细胞不表达这种异常 的周期蛋白E。（2）在乳腺癌细胞株之间,相对ER阳性的MCF－7细胞,ER阴性的MDA－MB－231细胞则高表达周期蛋白E,基本无表达P21蛋白。结论L（1）正常细胞与这间、相对低恶性程度的民相对高恶性和蔼的癌细胞之间的差别是多环节的、质和量异常导致的结果;（2）周期蛋白E及P21均可反映乳腺癌细胞的增殖活性和恶性程度,可能是乳腺癌的临床预后指标。     

Role of estrogen receptor in the regulation of ecto-5'-nucleotidase and adenosine in breast cancer.

PURPOSE: The purpose is to understand the expression of ecto-5'-nucleotidase (eN), an adenosine producing enzyme with potential roles in angiogenesis, growth, and immunosuppression, in estrogen receptor (ER)-negative and -positive breast cancer. EXPERIMENTAL DESIGN: We investigated the regulation of eN expression at the mRNA and protein levels by alpha in a panel of breast cancer cell lines that differ in ER status and invasive and metastatic potential. We also determined rates of adenosine formation in cells with high and low eN expression and in ER+ cells treated with estradiol. RESULTS: ER-negative cells express high eN protein and mRNA levels and produce up to 104-fold more adenosine from AMP and ATP. Estradiol and antiestrogen treatments confirm that eN mRNA and protein expression and adenosine generation are negatively regulated through the ER. Endogenous expression of eN in ER- cells transfected with ERalpha and phorbol ester-induced eN expression in ER+ cells was strongly suppressed by estradiol, suggesting a dominant function of ER. Finally, an examination of 18 clinical breast cancer samples that were analyzed for both ER status and eN expression by Martin et al. (Cancer Res., 60: 2232-2238, 2000) revealed a significant inverse correlation between ER and eN status. CONCLUSIONS: Our results show for the first time that eN is negatively regulated by ERalpha in dominant fashion and suggests that eN expression and its generation of adenosine may relate to breast cancer progression. Additionally, increased expression of eN in a subset of ER-negative cells may serve as a novel marker for a subset of more aggressive breast carcinoma.     

nm23基因、雌孕激素受体在乳腺癌中的表达及临床意义

目的研究nm23基因,ER、PR在乳腺癌中的表达及临床意义.方法应用免疫组化染色对65例资料完整有7年随访结果的原发性乳腺癌nm23基因表达,ER、PR进行检测.结果65例患者nm23基因高表达36例,低表达29例.转移和非转移组nm23基因低与高表达有显著性差异(P<0.005),nm23低表达易发生转移.生存5年以下和5年以上的两组患者nm23的表达水平有显著性差异(P<0.005),高表达者比低表达者预后好;本研究未发现nm23表达与年龄,病理类型、临床分期的相关性;65例患者ER(+)PR(+)者33例,ER(-)、PR(-)者16例,两组之间nm23高表达和低表达存在着显著性差异(P<0.005).结论nm23基因表达和乳腺癌的转移呈负相关,和预后呈正相关.联合考虑nm23基因的表达高低和强度,才能更合理的判定转移,并可筛选出具有潜在高转移危险的患者;在判断转移和预后方面,ER(+)PR(+)与nm23基因高表达之间存在着正相关性,ER(-)PR(-)和nm23基因低表达之间存在着正相关性.     

ERα和ERβ在乳腺癌组织中的表达及临床意义

目的:观察ERα和ERβ蛋白表达与乳腺癌临床病理参数的相关性及临床意义。方法:收集散发性乳腺癌标本214例,乳腺纤维腺瘤组织25例,应用SP免疫组化法检测ERα和ERβ蛋白的表达情况,并分析与乳腺癌患者临床指标及病理参数的相关性。结果:乳腺癌中ERα、ERβ蛋白表达阳性率分别为56.5%（121/214）、62.1%（133/214）,乳腺纤维腺瘤中ERα、ERβ蛋白表达阳性率分别76.0%（19/25）、84.0%（21/25）,与乳腺纤维腺瘤组织比较,乳腺癌组织ERα蛋白阳性表达率无差异,ERβ蛋白阳性表达率显著低于乳腺纤维腺瘤组织（P=0.031）。在乳腺癌组织中,ERα蛋白表达水平与患者年龄、病理类型、临床分级及淋巴结转移、HER-2、p53蛋白表达均未见相关性,与PR蛋白表达正相关（P<0.000 1）。 ERβ蛋白表达与患者年龄和绝经状态相关,在不同的病理类型中,浸润性小叶癌的ERβ蛋白表达阳性率明显高于其它类型肿瘤（P=0.029）;ERβ蛋白表达与临床分级、淋巴结转移情况、HER-2、p53蛋白表达比较均未见相关性。生存分析发现,ERα和ERβ蛋白表达对乳腺癌患者总体生存期未见显著影响,ERα和ERβ均阳性表达的乳腺癌患者,OS时间明显延长（P<0.05）。结论:ERα、ERβ蛋白在乳腺癌组织的异常表达与患者年龄、绝经状态、病理类型相关,二者协同表达对于乳腺癌的发生和发展更具指导意义。