Guillot C, Falette N, Paperin M P, Courtois S, Gentil-Perret A, Treilleux I, Ozturk M, Puisieux A
INSERM U453, Centre Léon Bérard, Lyon, France.
Oncogene. 1997 Jan 9;14(1):45-52. doi: 10.1038/sj.onc.1200803.
Functional inactivation of the wild-type p53 protein has been described in different human cancers. Since a significant proportion of breast tumours express wild-type TP53, the p53 antiproliferative activity could be inactivated in transformed mammary epithelial cells by a mechanism independent on structural alteration of the gene. To test this hypothesis, we analysed the p53 activity in primary breast tumour cells. As a preliminary study, we demonstrated in breast adenocarcinoma cell lines that the nuclear accumulation of the inhibitor of cyclin dependent kinase p21(WAFl/CIP1), in response to adriamycin treatment, specifically reflected the activity of a functional wild-type p53 protein. Then, we used this strategy to study the p53 activity in 23 primary breast tumours. p21(WAF1/CIP1 accumulation was detected in all tumours expressing wild-type TP53. In contrast, no p21(WAF1/CIP1) response was detected in cells harboring a mutant TP53 gene. This report is the first functional study of p53 in primary breast tumours. The results demonstrate that TP53 mutation represents the only common mechanism leading to an irreversible inactivation of p53 functions in this cancer type.
野生型p53蛋白的功能失活已在不同的人类癌症中被描述。由于相当一部分乳腺肿瘤表达野生型TP53，p53的抗增殖活性可能在转化的乳腺上皮细胞中通过一种不依赖于该基因结构改变的机制而失活。为了验证这一假设，我们分析了原发性乳腺肿瘤细胞中的p53活性。作为一项初步研究，我们在乳腺腺癌细胞系中证明，响应阿霉素治疗，细胞周期蛋白依赖性激酶抑制剂p21（WAFl/CIP1）的核积累特异性反映了功能性野生型p53蛋白的活性。然后，我们使用这种策略研究了23例原发性乳腺肿瘤中的p53活性。在所有表达野生型TP53的肿瘤中均检测到p21（WAF1/CIP1）积累。相反，在携带突变型TP53基因的细胞中未检测到p21（WAF1/CIP1）反应。本报告是对原发性乳腺肿瘤中p53的首次功能研究。结果表明，TP53突变是导致该癌症类型中p53功能不可逆失活的唯一常见机制。
