Roos G, Nilsson P, Cajander S, Nielsen N H, Arnerlöv C, Landberg G
Department of Pathology, Umeå University, Sweden.
Int J Cancer. 1998 Aug 21;79(4):343-8. doi: 10.1002/(sici)1097-0215(19980821)79:4<343::aid-ijc6>3.0.co;2-v.
Cell cycle deregulation can occur at different levels in cancer. In human breast cancer it includes overexpression of cyclins D1 and E, down-regulation of cyclin-dependent kinase inhibitors and inactivation of the retinoblastoma and p53 tumor suppressor proteins. Telomerase activity is strongly associated with an immortal phenotype and expression of telomerase is linked to the cell cycle. We have recently demonstrated a connection between specific cell cycle defects within the pRB pathway and levels of telomerase activity in breast cancer. In the present study, 106 tumors were investigated for p53 gene and protein status. By single strand conformation polymorphism (SSCP) analysis, 15% showed mutations within exons 5-8 and by immunohistochemistry (IHC), 29% were p53 positive. Tumors with a telomerase activity above median (i.e., telomerase(high)) were significantly associated with p53 protein accumulation (p = 0.004), but not with p53 gene mutations. The strongest telomerase expression was found in tumors with p53 protein accumulation. Morphologic grade, estrogen and progesterone receptor expression differed significantly between the telomerase(high) and telomerase(low) groups (p < 0.0001, p = 0.016 and p = 0.046, respectively), but no difference was observed for stage or nodal status. Telomerase(high) tumors were significantly associated with a poor prognosis for node-negative (N0) patients (p = 0.008), but not for node-positive (N+) patients, whereas the opposite was demonstrated for tumors with p53 accumulation. The survival data indicated that telomerase expression has biological importance particularly for N0 tumors, suggesting that telomerase(low) tumors constitute a group of "pre-immortalized" tumors with a good prognosis.
细胞周期失调可在癌症的不同层面发生。在人类乳腺癌中，它包括细胞周期蛋白D1和E的过表达、细胞周期蛋白依赖性激酶抑制剂的下调以及视网膜母细胞瘤和p53肿瘤抑制蛋白的失活。端粒酶活性与永生表型密切相关，端粒酶的表达与细胞周期相关。我们最近证明了pRB通路内特定细胞周期缺陷与乳腺癌中端粒酶活性水平之间的联系。在本研究中，对106个肿瘤的p53基因和蛋白状态进行了研究。通过单链构象多态性（SSCP）分析，15%的肿瘤在外显子5-8内显示出突变，通过免疫组织化学（IHC）分析，29%的肿瘤p53呈阳性。端粒酶活性高于中位数的肿瘤（即端粒酶（高））与p53蛋白积累显著相关（p = 0.004），但与p53基因突变无关。在有p53蛋白积累的肿瘤中发现最强的端粒酶表达。端粒酶（高）组和端粒酶（低）组之间的形态学分级、雌激素和孕激素受体表达存在显著差异（分别为p < 0.0001、p = 0.016和p = 0.046），但在分期或淋巴结状态方面未观察到差异。端粒酶（高）肿瘤与淋巴结阴性（N0）患者的预后不良显著相关（p = 0.008），但与淋巴结阳性（N+）患者无关，而对于有p53积累的肿瘤则表现相反。生存数据表明，端粒酶表达尤其对N0肿瘤具有生物学重要性，提示端粒酶（低）肿瘤构成一组预后良好的“预永生”肿瘤。
