Bouchalova Pavla, Nenutil Rudolf, Muller Petr, Hrstka Roman, Appleyard M Virginia, Murray Karen, Jordan Lee B, Purdie Colin A, Quinlan Philip, Thompson Alastair M, Vojtesek Borivoj, Coates Philip J
Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
J Pathol. 2014 Jul;233(3):238-46. doi: 10.1002/path.4356. Epub 2014 May 21.
Many human cancers contain missense TP53 mutations that result in p53 protein accumulation. Although generally considered as a single class of mutations that abrogate wild-type function, individual TP53 mutations may have specific properties and prognostic effects. Tumours that contain missense TP53 mutations show variable p53 stabilization patterns, which may reflect the specific mutation and/or aspects of tumour biology. We used immunohistochemistry on cell lines and human breast cancers with known TP53 missense mutations and assessed the effects of each mutation with four structure-function prediction methods. Cell lines with missense TP53 mutations show variable percentages of cells with p53 stabilization under normal growth conditions, ranging from approximately 50% to almost 100%. Stabilization is not related to structural or functional disruption, but agents that stabilize wild-type p53 increase the percentages of cells showing missense mutant p53 accumulation in cell lines with heterogeneous stabilization. The same heterogeneity of p53 stabilization occurs in primary breast cancers, independent of the effect of the mutation on structural properties or functional disruption. Heterogeneous accumulation is more common in steroid receptor-positive or HER2-positive breast cancers and cell lines than in triple-negative samples. Immunohistochemcal staining patterns associate with Mdm2 levels, proliferation, grade and overall survival, whilst the type of mutation reflects downstream target activity. Inhibiting Mdm2 activity increases the extent of p53 stabilization in some, but not all, breast cancer cell lines. The data indicate that missense mutant p53 stabilization is a complex and variable process in human breast cancers that associates with disease characteristics but is unrelated to structural or functional properties. That agents which stabilize wild-type p53 also stabilize mutant p53 has implications for patients with heterogeneous mutant p53 accumulation, where therapy may activate mutant p53 oncogenic function.
许多人类癌症都含有错义TP53突变，导致p53蛋白积累。虽然通常被认为是一类消除野生型功能的单一突变，但个别TP53突变可能具有特定特性和预后影响。含有错义TP53突变的肿瘤表现出可变的p53稳定模式，这可能反映了特定突变和/或肿瘤生物学的某些方面。我们对具有已知TP53错义突变的细胞系和人类乳腺癌进行了免疫组织化学分析，并使用四种结构-功能预测方法评估了每种突变的影响。具有错义TP53突变的细胞系在正常生长条件下显示出p53稳定的细胞百分比各不相同，范围从约50%到几乎100%。稳定化与结构或功能破坏无关，但稳定野生型p53的药物会增加在具有异质性稳定化的细胞系中显示错义突变型p53积累的细胞百分比。原发性乳腺癌中也存在相同的p53稳定异质性，与突变对结构特性或功能破坏的影响无关。异质性积累在类固醇受体阳性或HER2阳性乳腺癌及细胞系中比在三阴性样本中更常见。免疫组织化学染色模式与Mdm2水平、增殖、分级和总生存期相关，而突变类型反映下游靶标活性。抑制Mdm2活性会增加某些但并非所有乳腺癌细胞系中p53稳定的程度。数据表明，错义突变型p53稳定化在人类乳腺癌中是一个复杂且可变的过程，与疾病特征相关，但与结构或功能特性无关。稳定野生型p53的药物也能稳定突变型p53，这对具有异质性突变型p53积累的患者具有重要意义，因为治疗可能会激活突变型p53的致癌功能。
