环氧合酶-2与乳腺癌的关系

研究发现乳腺癌组织内环氧合酶（COX）-2的表达与乳腺癌的发生、发展及预后有关。COX-2的表达可能增加乳腺癌细胞的活性和侵袭力,增加前列腺素产物的生成,抑制乳腺癌细胞的凋亡等。因此,COX-2抑制剂可能成为防治乳腺癌的新物质。     

乳腺癌还氧合酶-2表达的研究现状

还氧合酶-2(COX-2)过表达与很多肿瘤发生发展有关。最近研究显示COX-2在乳腺癌细胞株和组织标本中表达增加,提示COX-2可能直接参与乳腺癌的形成,并且与预后有关。因此,应用COX-2抑制剂治疗乳腺癌成为目前的研究热点。     

乳腺癌还氧合酶-2表达的研究现状

还氧合酶-2（COX-2）过表达与很多肿瘤发生发展有关。最近研究显示COX-2在乳腺癌细胞株和组织标本中表达增加，提示COX-2可能直接参与乳腺癌的形成，并且与预后有关。因此，应用COX-2抑制剂治疗乳腺癌成为目前的研究热点。     

环加氧酶-2 通过调控EMT促进乳腺癌MDA-MB-231 细胞的迁移和侵袭

[摘要] 目的：探讨环加氧酶-2（COX-2）在乳腺癌转移中的作用及其可能的机制。方法：收集从2015 年10 月至2018 年4 月在云南省肿瘤医院接受乳腺切除术的患者中获得的原发乳腺癌组织和脑转移乳腺癌组织临床病理样本共45 例,其中原发30 例、脑转移15 例。采用qPCR检测COX-2 在原位乳腺癌和脑转移乳腺癌组织中的表达。将COX-2 过表达重组病毒（LV6-COX2）或敲减COX-2 重组病毒（LV3-COX2 shRNA1、LV3-COX2 shRNA2）感染人乳腺癌MDA-MB-231 细胞并获得稳转细胞株后,CCK-8法检测COX-2 表达对MDA-MB-231 细胞增殖的影响,划痕实验和Transwell 法检测对MDA-MB-231 细胞迁移和侵袭的影响。qPCR和WB实验分析各组细胞中COX-2 mRNA和蛋白的表达水平,qPCR检测COX-2 表达对MDA-MB-231 细胞内EMT相关基因表达的影响。结果：COX-2 表达水平在脑转移乳腺癌患者组织中显著高于原位乳腺癌组织（P<0.01）;并且与乳腺癌患者肿瘤TMN分期有关。成功构建稳定过表达/敲减COX-2 的MDA-MB-231 细胞株。过表达COX-2 促进MDA-MB-231 细胞的迁移和侵袭（均P<0.01）,同时显著提高MMP2、MMP1、N-cadherin 和vimentin 的表达（均P<0.01）,但对细胞增殖无明显影响;而沉默COX-2 则有相反的作用,且可促进细胞增殖（P<0.05）。结论：COX-2 在脑转移乳腺癌组织中高表达,其可能通过调控EMT过程促进乳腺癌MDA-MB-231 细胞的迁移和侵袭。     

环氧化酶-2在人、大鼠乳腺癌及人乳腺癌细胞株的表达及其意义

 目的 探讨环氧化酶-2（COX-2）在人、大鼠乳腺癌及人乳腺癌细胞株的表达及其意义。方法 应用免疫组织化学、Western bloting、RT-PCR法检测人乳腺癌组织及配对的癌旁组织、大鼠致癌组、选择性COX-2抑制剂尼美舒利（NIM）组、人乳腺癌细胞株中COX-2的表达，MMT法检测细胞株的生长率。结果 正常人、大鼠乳腺组织不表达COX-2m RNA、蛋白，癌旁组织表达明显增高，肿瘤组织COX-2 mRNA、蛋白显著增高，NIM明显下调大鼠乳腺癌COX-2的表达；MDA-MB-231细胞COX-2呈强表达，MCF-7细胞不表达COX-2；NIM显著抑制MCF-7、MDA-MB-231细胞的增生。结论 COX-2可作为预防乳腺癌的分子靶点；NIM对MDA-MB-231细胞的抑制更为有效，提示COX-2选择性抑制剂对ER（-）的乳腺癌有更好的预防作用，COX-2的分子靶向治疗将成为乳腺癌预防和治疗的新途径。     

VEGF-C与COX-2反义寡核苷酸联合抑制乳腺癌细胞VEGF-C的表达

目的：探讨以阳离子脂质体（liposomes,LIP）为载体联合转染VEGF-C与COX-2的反义寡核苷酸（antisense oligonudeotides,ASODN）对乳腺癌细胞MDA-MB-231中VEGF-C表达的影响。方法：MTT法检测ASODN对细胞的毒性作用并确定最佳转染浓度,RT-PCR法检测联合转染VEGF-C与COX-2 ASODN后对乳腺癌细胞中VEGF-C mRNA表达的影响,免疫组织化学及激光共聚焦法检测联合转染后乳腺癌细胞VEGF-C蛋白的表达。结果：ASODN＋LIP以浓度0.2mmol/L＋2.5mL/L转染时对细胞无明显毒性作用;联合组对VEGF-C mRNA的抑制率为70.37%,单用VEGF-C及COX-2ASODN组分别为48.15%及42.21%,联合组对VEGF-C mRNA的抑制率显著高于单用ASODN组（P〈0.01）;联合组乳腺癌细胞中VEGF-C蛋白的表达明显低于单用VEGF-C及COX-2 ASODN组（P〈0.01）。结论：联合转染VEGF-C与COX-2 ASODN可明显降低乳腺癌细胞MDA-MB-231中VEGF-C mRNA及蛋白水平。COX-2可能参与并诱导了乳腺癌细胞VEGF-C的表达。     

乳腺癌中COX-2表达及其抑制剂塞来昔布对乳腺癌细胞系增生和凋亡的影响

目的为进一步观察COX-2对乳腺癌的作用,我们检测了乳腺癌组织、乳腺癌细胞株MCF-7和B37中COX-2的表达,并观察选择性COX-2抑制剂塞来昔布对乳腺癌细胞株生长和凋亡的影响。方法应用免疫组织化学染色的方法检测132例乳腺癌组织标本中COX-2蛋白的表达;应用免疫细胞化学染色、原位杂交、逆转录多聚酶联反应（RT-PCR）的方法,分别检测COX-2蛋白和mRNA在乳腺癌细胞株MCF-7、B37中的表达;采用MTT法、AO/EB双荧光染色法和流式细胞术,研究塞来昔布对乳腺癌细胞增殖和凋亡的影响。结果52.3%(69/132)的乳腺癌组织标本表达COX-2蛋白;在乳腺癌细胞株MCF-7和B37中均有COX-2的表达,25μmol/L塞来昔布作用72h后,COX-2表达明显减少;25、50、100μmol/L的塞来昔布与MCF-7细胞作用72h,生长抑制率分别为36.3%、57.7%、74.5%。100μmol/L塞来昔布作用72h后,MCF-7细胞凋亡率为38.5％。结论乳腺癌组织和乳腺癌细胞株MCF-7、B37中存在COX-2的表达;塞来昔布可抑制乳腺癌细胞增殖,并促进细胞凋亡,塞来昔布可能作为新的药物治疗乳腺癌。     

乳腺癌组织COX-2表达及其与肿瘤多药耐药关系的研究

目的:通过观测环氧合酶-2(COX-2)抑制剂尼美舒利(Nimesulide)对人乳腺癌细胞株MDA-MB-231的化疗药物敏感性及其对P-糖蛋白(P-gp)表达的影响,探讨COX-2对乳腺癌细胞多药耐药(MDR)的调节作用。方法:以乳腺癌细胞株MDA-MB-231为研究对象,用MTT法研究COX-2抑制剂Nimesulide单独及联合不同浓度的丝裂霉素(MMC)对MDA-MB-231的抑制作用(IC50),流式细胞技术检测细胞凋亡率及COX-2和P-gp的表达变化。结果:MMC单独作用于乳腺癌细胞株MDA-MB-231,MMC对细胞的IC50为8.59±1.16,25μmol/L的Nimesulide与MMC联合作用,IC50减少5.89±0.66,差异有统计学意义,P=0.002;50μmol/L的Nimesulide与MMC联合作用,IC50进一步减少3.31±0.30,与25μmol/L比较,差异有统计学意义,P=0.003。说明Nimesulide能增加MMC对MDA-MB-231的化疗敏感性,这种作用与Nime-sulide呈剂量依赖性。流式细胞仪分析发现,Nimesulide可诱导细胞凋亡,且随着浓度的增加,凋亡率也随之增加(由0.13±0.15增加到29.2±0.95),差异有统计学意义,F=44.84,P=0.000。Nimesulide作用于MDA-MB-231细胞后,COX-2和P-gp的表达同时下降,COX-2的表达由70.37±1.98降低为9.60±2.11,P-gp的表达由14.13±2.63降低为0.43±0.15,差异均有统计学意义,P值均<0.05。结论:Nimesulide能明显增加MMC对乳腺癌细胞株MDA-MB-231的化疗敏感性,COX-2与肿瘤MDR密切相关,且可能通过P-gp来实现。     

Nimesulide对乳腺癌细胞株化疗敏感性的影响及机制研究

目的：探讨选择性环氧化酶2（cy-clooxygenase-2，COX-2）抑制剂nimesulide对乳腺癌细胞株化疗敏感性的影响，同时探讨其可能机制。方法：利用体外培养的乳腺癌细胞株MDA-MB-231、MCF-7，MTT法比较多柔比星（ADM）及联合不同浓度的nimesulide对两种细胞抑制率的影响（IC50）；应用逆转录聚合酶链反应（RT-PCR）观察不同浓度nimesulide对两种细胞多药耐药蛋白（MDR1）mRNA的影响。结果：Nimesulide能增加ADM对MDA-MB-231、MCF-7的细胞毒作用，这种作用与nimesulide呈剂量依赖性，对COX-2高表达的MDA-MB-231细胞更加敏感；nimesulide能降低MDR1 mRNA的表达水平，并呈剂量依赖性（10、25、50μmol／L nimesulide）。结论：选择性COX-2抑制剂nimesulide能增加ADM对MDA-MB-231、MCF-7的细胞毒作用，这种作用可能与MDR1水平的下调有关，为选择性COX-2抑制剂联合细胞毒药物用于乳腺癌的化疗提供了实验依据。     

COX-2、p53和C-erbB-2在乳腺癌组织中的表达及其临床意义

目的:探讨COX-2、p53和C-erbB-2与乳腺癌的关系.方法:用免疫组化方法检测96例乳腺癌标本中COX-2、p53和C-erbB-2的表达情况并结合临床病理特征分析.结果:三者在乳腺癌组织中均表达阳性,且三者阳性表达与淋巴结转移、肿瘤直径、ER阴性、乳腺癌临床分期有关.提示三者表达均可作为判断乳腺癌预后的指标,联合检测可更好的评价乳腺癌的预后.同时p53和C-erbB-2阳性表达在COX-2阳性表达的乳腺癌标本中表达尤为明显.结论: COX-2和p53、C-erbB-2阳性表达之间可能存在某种互调机制,为COX-2特异性免疫抑制剂治疗乳腺癌提供了新的思路.     

COX-2 involvement in breast cancer metastasis to bone

Cyclooxygenase-2 (COX-2) is expressed in 40% of human invasive breast cancers. Bone is the predominant site of metastasis in case of breast cancer. We investigated the role of COX-2 in a suitable mouse model of breast cancer metastasis to bone using the whole-body luciferase imaging of cancer cells. We provide several lines of evidence that COX-2 produced in breast cancer cells is important for bone metastasis in this model including (1) COX-2 transfection enhanced the bone metastasis of MDA-435S cells and (2) breast cancer cells isolated and cultured from the bone metastases produced significantly more prostaglandin E(2) (an important mediator of COX-2) than the parental injected cell populations of breast cancer cells. Next, we found that a COX-2 inhibitor, MF-tricyclic, inhibited bone metastasis caused by a bone-seeking clone both in prevention regimen (in which case mice started receiving MF-tricyclic 1 week before the injection of cancer cells) and in treatment regimen (in which case mice received MF-tricyclic after the development of bone metastasis). These studies indicate that COX-2 produced in breast cancer cells may be vital to the development of osteolytic bone metastases in patients with breast cancer, and that COX-2 inhibitors may be useful in halting this process.     

Cyclooxygenase-2 expression correlates with diminished survival in invasive breast cancer treated with mastectomy and radiotherapy

PURPOSE: To evaluate the relationship between cyclooxygenase-2 (COX-2) expression and pathologic features and outcome in invasive breast cancer. METHODS AND MATERIALS: Formalin-fixed, paraffin-embedded tumor specimens from 23 women with invasive breast cancer were stained for COX-2 expression. All women underwent mastectomy and locoregional radiotherapy. The distribution (percentage of positive staining cells) and intensity of COX-2 expression within the tumor cells were compared with clinical factors, including stage, grade, lymph node involvement, and outcome. RESULTS: For invasive breast cancer, the distribution and intensity of COX-2 tumor expression correlated significantly with diminished overall survival. The 5-year overall survival rate was 100% for patients with <75% of breast cancer cells expressing COX-2 compared with 49% for patients with > or =75% (p = 0.044). The 5-year overall survival rate was 100% for patients with COX-2 intensity <80 compared with 60% for patients with COX-2 intensity > or =80 (p = 0.018). The percentage and intensity of COX-2 expression also correlated significantly with disease-free survival. The percentage of cells expressing COX-2 was significantly greater in women <40 years old than in women > or =40 years old (81% vs. 59%, respectively, p = 0.04). CONCLUSION: Both the distribution and the intensity of COX-2 expression correlated significantly with disease-free and overall survival in patients with invasive breast cancer. Younger patients with invasive breast cancer may have a greater percentage of COX-2 expression in their tumors.     

Silencing of COX-2 by RNAi Modulates Epithelial-Mesenchymal Transition in Breast Cancer Cells Partially Dependent on the PGE2 Cascade

In order to prove whether downregulation of COX-2 (Cyclooxygenase-2) could modulate the epithelialmesenchymaltransition (EMT) of breast cancer, celecoxib and siRNA were respectively used to inhibit COX-2function and expression in MDA-MB-231 cells. The EMT reversal effect in the RNAi treated group was betterthan that of the celecoxib group while there were no obvious differences in the medium PGE2 levels betweenthe two groups. The results show that COX-2 pathways may contribute considerably to EMT of breast cancercells, partially dependent on the PGE2 cascade. Akt2, ZEB2 and Snail were measured to clarify the underlyingmechanisms of COX-2 on EMT; COX-2 may modulate EMT of breast cancer by regulating these factors. Thisfinding may be helpful to elucidate the mechanisms of selective COX-2 inhibitor action in EMT modulation inbreast cancer.     

Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells

Tumor-associated macrophages (TAMs) play an important role in cancer cell survival, however, the mechanism of which remains elusive. In this study, we found that COX-2 was abundantly expressed in breast TAMs, which was correlated to poor prognosis in breast cancer patients. Ectopic over-expression of COX-2 in TAMs enhanced breast cancer cell survival both in vitro and in vivo. COX-2 in TAMs was determined to be essential for the induction and maintenance of M2-phenotype macrophage polarity. COX-2⁺ TAMs promoted breast cancer cell proliferation and survival by increasing Bcl-2 and P-gp and decreasing Bax in cancer cells. Furthermore, COX-2 in TAMs induced the expression of COX-2 in breast cancer cells, which in turn promoted M2 macrophage polarization. Inhibiting PI3K/Akt pathway in cancer cells suppressed COX-2⁺ TAMs-induced cancer cell survival. These findings suggest that COX-2, functions as a key cancer promoting factor by triggering a positive-feedback loop between macrophages and cancer cells, which could be exploited for breast cancer prevention and therapy.     

Cyclooxygenase-2 expression during immortalization and breast cancer progression

Identification of molecular aberrations in premalignant human mammary epithelial cells (hMEC), the precursors for breast cancers, is a central goal in breast cancer biology. Recent studies implicated expression of cyclooxygenase 2 (COX-2) as a marker to identify precursor cells for breast cancer. In this study, we analyzed COX-2 expression in preselection and postselection hMEC cells and observed similar COX-2 levels in both cells. Interestingly, immortalization of postselection cells using various methods leads to a dramatic decrease in COX-2 expression. Similar to immortal cells, the majority of breast cancer cell lines expressed low levels of COX-2 protein. Finally, analyses of COX-2 expression in a series of specimens from reduction mammoplasty, adenosis, ductal carcinoma in situ, and infiltrating ductal carcinoma showed down-regulation of COX-2 expression during tumor progression. Importantly, down-regulation of COX-2 using small interfering RNA in cells showed no effect on cell proliferation, anchorage-independent growth, migration, or invasion. These results show that (a) COX-2 overexpression does not seem to predict a breast cancer precursor cell and does not provide advantage for the cell to be transformed; (b) inhibition of COX-2 does not affect hMEC growth and oncogenic behavior in the conditions analyzed; and (c) COX-2 expression is decreased in breast cancer cell lines and cancer specimens as compared with normal mammary epithelial cells.     

Cyclooxygenase-2 is essential for HER2/neu to suppress N- (4-hydroxyphenyl)retinamide apoptotic effects in breast cancer cells

We reported that HER2/neu reduces the sensitivity of breast cancer cells to N-(4-hydroxyphenyl)retinamide (4-HPR) by suppressing nitric oxide production. We show that HER2/neu uses Akt to induce cyclooxygenase-2 (COX-2) expression and that inhibition of Akt or COX-2 increases 4-HPR-induced apoptosis and nitric oxide production. Apoptosis induced by the 4-HPR and COX-2 inhibitor combination, although unaffected by an anti-HER2/neu antibody, was reversed by the COX-2 product prostaglandin E(2), indicating that COX-2 is a major mechanism by which HER2/neu suppresses 4-HPR apoptosis in breast cancer cells. Combining 4-HPR with COX-2 inhibitors may be a novel chemopreventive strategy against HER2/neu-overexpressing breast tumors.