A randomised controlled phase II trial of pre-operative celecoxib treatment reveals anti-tumour transcriptional response in primary breast cancer.
A randomised controlled phase II trial of pre-operative celecoxib treatment reveals anti-tumour transcriptional response in primary breast cancer.
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DOI：
10.1186/bcr3409
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发表时间：
2013-04-08
期刊：
影响因子：
--
通讯作者：
Hupperets PS
中科院分区：
文献类型：
--
作者：
Brandão RD;Veeck J;Van de Vijver KK;Lindsey P;de Vries B;van Elssen CH;Blok MJ;Keymeulen K;Ayoubi T;Smeets HJ;Tjan-Heijnen VC;Hupperets PS
环氧合酶-2(COX-2)在乳腺癌中经常过度表达。在转基因乳腺癌模型中，COX-2的过度表达导致肿瘤的形成，而COX-2的抑制在乳腺癌细胞系中发挥抗肿瘤作用。为了进一步确定COX-2抑制在原发性乳腺癌中的作用，我们的目的是确定选择性COX-2抑制剂塞来昔布治疗患者乳腺癌组织中转录的变化。在一项单中心、双盲的II期研究中，37名乳腺癌患者被随机分成两组，一组在两到三周内每天两次服用塞来昔布(400毫克)(n=22)，另一组按照相同的时间表服用安慰剂(n=15)。用Affymetrix阵列分析新鲜冷冻的手术前活组织(治疗前)和手术切除标本(治疗后)的基因表达。差异表达的基因和改变的途径被生物信息学鉴定。用定量聚合酶链式反应(QPCR)验证所选基因的表达。免疫组织化学检测增殖标记物Ki-67、凋亡标记物裂解caspase-3和新生血管生成标记物CD34的蛋白表达以评价生物学反应。在塞来昔布治疗的样本中，我们分别发现了972个和586个显著上调和下调的基因。在8个基因中，有6个基因的表达发生了显著变化，可以通过qPCR进行验证。通路分析显示，在增殖、细胞周期、细胞外基质生物学和炎性免疫反应网络中，非调控基因的过度表达。治疗组和对照组Ki-67平均变化分别为-29.1%(P=0.019)和-8.2%(P=0.384)。治疗组间Ki-67表达变化有统计学意义(P=0.029)。Caspase-3和CD34的表达在塞来昔布治疗组和安慰剂组之间没有显著差异。塞来昔布短期抑制COX-2可诱导原发乳腺癌组织中支持抗肿瘤活性的转录程序。对增殖相关基因的影响反映在Ki-67阳性细胞的减少上。因此，应考虑将抑制COX-2作为进一步临床试验的治疗策略。临床试验.gov NCT01695226。
Cyclooxygenase-2 (COX-2) is frequently over-expressed in primary breast cancer. In transgenic breast cancer models, over-expression of COX-2 leads to tumour formation while COX-2 inhibition exerts anti-tumour effects in breast cancer cell lines. To further determine the effect of COX-2 inhibition in primary breast cancer, we aimed to identify transcriptional changes in breast cancer tissues of patients treated with the selective COX-2 inhibitor celecoxib. In a single-centre double-blind phase II study, thirty-seven breast cancer patients were randomised to receive either pre-operative celecoxib (400 mg) twice daily for two to three weeks (n = 22) or a placebo according to the same schedule (n = 15). Gene expression in fresh-frozen pre-surgical biopsies (before treatment) and surgical excision specimens (after treatment) was profiled by using Affymetrix arrays. Differentially expressed genes and altered pathways were bioinformatically identified. Expression of selected genes was validated by quantitative PCR (qPCR). Immunohistochemical protein expression analyses of the proliferation marker Ki-67, the apoptosis marker cleaved caspase-3 and the neo-angiogenesis marker CD34 served to evaluate biological response. We identified 972 and 586 significantly up- and down-regulated genes, respectively, in celecoxib-treated specimens. Significant expression changes in six out of eight genes could be validated by qPCR. Pathway analyses revealed over-representation of deregulated genes in the networks of proliferation, cell cycle, extracellular matrix biology, and inflammatory immune response. The Ki-67 mean change relative to baseline was -29.1% (P = 0.019) and -8.2% (P = 0.384) in the treatment and control arm, respectively. Between treatment groups, the change in Ki-67 was statistically significant (P = 0.029). Cleaved caspase-3 and CD34 expression were not significantly different between the celecoxib-treated and placebo-treated groups. Short-term COX-2 inhibition by celecoxib induces transcriptional programs supporting anti-tumour activity in primary breast cancer tissue. The impact on proliferation-associated genes is reflected by a reduction of Ki-67 positive cells. Therefore, COX-2 inhibition should be considered as a treatment strategy for further clinical testing in primary breast cancer. ClinicalTrials.gov NCT01695226.
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影响因子：
158.5
作者：
GIOVANNUCCI, E;EGAN, KM;SPEIZER, FE
通讯作者：
SPEIZER, FE
DOI：
10.1016/j.ijrobp.2007.08.065
发表时间：
2008-01-01
影响因子：
7
作者：
Dittmann, Klaus H.;Mayer, Claus;Rodemann, H. Peter
通讯作者：
Rodemann, H. Peter
影响因子：
8.4
作者：
Auman, James Todd;Church, Robert;Mcleod, Howard L.
通讯作者：
Mcleod, Howard L.
影响因子：
2.1
作者：
da Silva, Benedito Borges;Pires, Cleicilene Gomes;Lopes-Costa, Pedro Vitor
通讯作者：
Lopes-Costa, Pedro Vitor
影响因子：
14.9
作者：
Dai M;Wang P;Boyd AD;Kostov G;Athey B;Jones EG;Bunney WE;Myers RM;Speed TP;Akil H;Watson SJ;Meng F
通讯作者：
Meng F