CIP2A Is Associated with Human Breast Cancer Aggressivity
CIP2A Is Associated with Human Breast Cancer Aggressivity
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DOI：
10.1158/1078-0432.ccr-08-3283
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发表时间：
2009-08-15
影响因子：
11.5
通讯作者：
Westermarck, Jukka
中科院分区：
文献类型：
--
作者：
Come, Christophe;Laine, Anni;Westermarck, Jukka
目的：研究新近发现的人癌蛋白-蛋白磷酸酶癌性抑制剂2A（CIP 2A）在人乳腺癌中的临床意义。实验设计：在三组不同的人乳腺肿瘤中测定CIP 2A的表达（mRNA和蛋白），并与临床病理变量进行比较。CIP 2A在乳腺癌细胞中的功能作用进行了评估小干扰RNA介导的蛋白质耗尽，然后通过分析细胞增殖，迁移，锚定独立的生长，和异种growth.Results：CIP 2A mRNA过表达（n = 159），并与较高的Scarff-布卢姆-Richardson等级（n = 251）在两个独立的人类乳腺癌患者的样本。CIP 2A蛋白在33例人乳腺癌中有39%过表达。此外，CIP 2A mRNA表达与患者的淋巴结阳性以及肿瘤样品中增殖标记物和p53突变的表达呈正相关。此外，在乳腺癌小鼠模型中诱导CIP 2A蛋白表达，该模型呈现乳腺特异性p53和BRCA 1或BRCA 2缺失。在功能上，CIP 2A耗竭显示抑制其靶蛋白c-Myc的表达。CIP 2A的缺失也抑制了乳腺癌细胞的锚定非依赖性生长。最后，CIP 2A被证明支持MDA-MB-231异种移植物在裸鼠中的生长。结论：我们的数据表明，CIP 2A与人类乳腺癌的临床侵袭性相关，并促进乳腺癌细胞的恶性生长。因此，这些结果验证了CIP 2A作为临床相关的人类癌蛋白的作用，并保证了CIP 2A作为乳腺癌治疗中的治疗靶点的进一步研究。(Clin Cancer Res 2009;15（16）：5092-100）
Purpose: To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer.Experimental Design: CIP2A expression (mRNA and protein) was measured in three different sets of human mammary tumors and compared with clinicopathologic variables. The functional role of CIP2A in breast cancer cells was evaluated by small interfering RNA-mediated depletion of the protein followed by an analysis of cell proliferation, migration, anchorage-independent growth, and xenograft growth.Results: CIP2A mRNA is overexpressed (n = 159) and correlates with higher Scarff-Bloom-Richardson grades (n = 251) in samples from two independent human breast cancer patients. CIP2A protein was found to be overexpressed in 39% of 33 human breast cancer samples. Furthermore, CIP2A mRNA expression positively correlated with lymph node positivity of the patients and with the expression of proliferation markers and p53 mutations in the tumor samples. Moreover, CIP2A protein expression was induced in breast cancer mouse models presenting mammary gland-specific depletion of p53 and either BRCA1 or BRCA2. Functionally, CIP2A depletion was shown to inhibit the expression of its target protein c-Myc. Loss of CIP2A also inhibited anchorage-independent growth in breast cancer cells. Finally, CIP2A was shown to support MDA-MB-231 xenograft growth in nude mice.Conclusions: Our data show that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells. Thus, these results validate the role of CIP2A as a clinically relevant human oncoprotein and warrant further investigation of CIP2A as a therapeutic target in breast cancer treatment. (Clin Cancer Res 2009;15(16):5092-100)