Landberg G, Nielsen N H, Nilsson P, Emdin S O, Cajander J, Roos G
Department of Pathology, Umeå University, Sweden.
Cancer Res. 1997 Feb 1;57(3):549-54.
Deregulation of the cell cycle by abnormal expression of one or several cell cycle regulatory proteins is a common finding in malignant tumors and might be a prerequisite for cancer development. Telomerase activity is an immortalization marker that is found in most cancers and for which an association with an active cell cycle has been implicated. In the tissue of 106 human breast carcinomas, we analyzed the relationship between telomerase activity levels and defects in the cell cycle machinery with a focus on the retinoblastoma protein (pRB) pathway(s). The fraction of telomerase-positive tumors was 85%, and large differences in telomerase activity were found. Overexpression of cyclin D1 and/or cyclin E, in combination with a normal pRB, was a typical feature of tumors with high telomerase activity levels. Down-regulation of p16INK4 was not related per se to telomerase activity, but tumors with low p16INK4 in combination with cyclin D1 or E overexpression demonstrated high activity. Tumor cell proliferation, determined by Ki-67 expression, correlated significantly to telomerase activity levels. There was, however, not a strict association between proliferation rate and telomerase activity, because tumors with inactivated pRB had the highest Ki-67 fractions but intermediate telomerase activity. Also, cyclin D1 overexpression was associated with high telomerase levels without an increase in tumor cell proliferation. The present study indicates that telomerase activation occurs preferentially in breast cancers with certain cell cycle regulatory defects and that telomerase activity levels may depend on the specific defect(s).
一种或几种细胞周期调节蛋白的异常表达导致细胞周期失调，这在恶性肿瘤中很常见，可能是癌症发生的先决条件。端粒酶活性是一种在大多数癌症中都能发现的永生化标志物，并且已经发现它与活跃的细胞周期有关。在106例人类乳腺癌组织中，我们分析了端粒酶活性水平与细胞周期机制缺陷之间的关系，重点关注视网膜母细胞瘤蛋白（pRB）途径。端粒酶阳性肿瘤的比例为85%，并且发现端粒酶活性存在很大差异。细胞周期蛋白D1和/或细胞周期蛋白E的过表达，与正常的pRB相结合，是端粒酶活性水平高的肿瘤的典型特征。p16INK4的下调本身与端粒酶活性无关，但p16INK4低表达且伴有细胞周期蛋白D1或E过表达的肿瘤表现出高活性。通过Ki-67表达确定的肿瘤细胞增殖与端粒酶活性水平显著相关。然而，增殖率与端粒酶活性之间并没有严格的关联，因为pRB失活的肿瘤具有最高的Ki-67分数，但端粒酶活性处于中等水平。此外，细胞周期蛋白D1过表达与高端粒酶水平相关，但肿瘤细胞增殖没有增加。本研究表明，端粒酶激活优先发生在具有某些细胞周期调节缺陷的乳腺癌中，并且端粒酶活性水平可能取决于特定的缺陷。
