An antisense oligodeoxynucleotide to p21(Waf1/Cip1) causes apoptosis in human breast cancer cells.-猫眼课题宝

DOI：

--

发表时间：

2003

期刊：

Molecular cancer therapeutics

影响因子：

5.7

通讯作者：

中科院分区：

医学2区

文献类型：

--

作者：

Yaping Fan;A. Borowsky;R. Weiss

尽管40%的人乳腺癌含有肿瘤抑制蛋白p53突变，但使用证明p53突变存在的试验作为乳腺癌的预后标志物并没有改变临床管理。因此，寻找新的标志物，特别是在细胞周期调控分子中，是一个高度优先的，无论是在阐明和识别新的目标。p21调节p53对DNA损伤反应的结果，正如给予化疗剂后可能发生的那样，我们已经证明，使用反义寡脱氧核苷酸（ODN）减弱p21可以抑制体外细胞增殖并减少Met-1的生长小鼠乳腺癌。在目前的研究中，我们将这项工作扩展到人体细胞和组织。我们从组织库中获得的8个人乳腺肿瘤中有3个显示出显著增加的p21水平，细胞核和胞质中的p21染色。所有相应的正常组织均为p21阴性。在三个p21阳性肿瘤中，磷脂酰肌醇3 '-激酶相关信号蛋白p85和PTEN也增加。为了研究p21是否是人乳腺癌中减毒的可行靶点，我们研究了两种人癌细胞系。当用反义p21 ODN转染时，MCF 7和T47 D乳腺癌细胞都表现出p21水平的剂量依赖性衰减，在没有额外的凋亡刺激的情况下与凋亡相关。由于p21调节细胞对受损DNA的修复反应，我们的工作表明，使用我们的反义p21 ODN减弱p21可能有效地调节乳腺癌的进展，无论是否存在联合化疗，并为未来的临床试验奠定了基础。

Whereas 40% of human breast carcinomas harbor mutations in the tumor suppressor protein p53, the use of tests demonstrating the presence of p53 mutations as a prognostic marker in breast cancer has not altered clinical management. Therefore, the search for new markers, especially among cell cycle-regulatory molecules, is a high priority, both in terms of prognostication and for identification of novel targets. p21 regulates the outcome of the p53 response to DNA damage, as might occur after administration of a chemotherapeutic agent, and we have shown that attenuation of p21 using an antisense oligodeoxynucleotide (ODN) inhibits cell proliferation in vitro and decreases growth of Met-1 mammary carcinomas in mice. In the current study, we extend this work to human cells and tissue. Three of eight human breast tumors that we obtained from a tissue bank show markedly increased p21 levels, variably staining in the nucleus and cytosol. All corresponding normal tissues were p21 negative. In the three p21-positive tumors, the phosphatidylinositol 3'-kinase-relevant signaling proteins p85 and PTEN were also increased. To investigate whether p21 is a feasible target for attenuation in human breast cancer, we investigated two human carcinoma cell lines. When transfected with antisense p21 ODN, both MCF7 and T47D breast cancer cells exhibit dose-dependent attenuation of p21 levels, associated with apoptosis in the absence of an additional apoptotic stimulus. Because p21 regulates the cellular repair response to damaged DNA, our work suggests that attenuation of p21 using our antisense p21 ODN may be effective in modulating the progression of breast cancer in either the presence or absence of combination chemotherapy and sets the stage for future clinical trials.