Nielsen N H, Emdin S O, Cajander J, Landberg G
Department of Pathology, Umeå University, Sweden.
Oncogene. 1997 Jan 23;14(3):295-304. doi: 10.1038/sj.onc.1200833.
Inactivation of the retinoblastoma protein (pRB) by mutations or abnormal phosphorylation is a mechanism by which tumour cells can subdue normal growth control. Among molecules involved in control of pRB phosphorylation, cyclin D1 and E have been found to be deregulated and overexpressed in various types of cancers. In order to study the cell cycle regulatory mechanisms in breast cancer, we have analysed the protein expression of cyclin D1 and E in 114 tumour specimens from patients with primary breast cancer using Western blotting. Twenty-five out of 34 tumours with overexpression of cyclin E showed uniform low cyclin D1 expression, and by immunohistochemical analysis of pRB we present evidence for the existence of pRB defects in approximately 40% of these tumours in contrast to no pRB defects in the other group of tumours. This result was supported by a high protein expression of the cyclin-dependent kinase inhibitor p16 in 44% of the tumours with high cyclin E and low D1 expression, and all immunohistochemical pRB defect tumours showed a high p16 protein level. Additionally, an abnormal low pRB phosphorylation in relation to a high proliferative activity and loss of heterozygosity of the retinoblastoma susceptibility gene locus were found in all but one tumour with immunohistochemical defect pRB. Interestingly, tumours with high cyclin E and low D1 expression were generally oestrogen receptor negative suggesting a role for cell cycle regulators in the mechanisms leading to oestrogen independent tumour growth. Furthermore, the prognosis differed markedly for the patients in the various groups of tumours, indicating that the heterogeneous nature of breast cancer pathogenesis and the clinical course in part could be explained by different and distinctive sets of cell cycle defects.
视网膜母细胞瘤蛋白（pRB）因突变或异常磷酸化而失活，是肿瘤细胞能够突破正常生长控制的一种机制。在参与控制pRB磷酸化的分子中，细胞周期蛋白D1和E已被发现在各类癌症中失调并过度表达。为了研究乳腺癌中的细胞周期调控机制，我们使用蛋白质免疫印迹法分析了114例原发性乳腺癌患者肿瘤标本中细胞周期蛋白D1和E的蛋白表达。在34例细胞周期蛋白E过表达的肿瘤中，有25例显示细胞周期蛋白D1表达一致偏低，通过对pRB进行免疫组化分析，我们发现这些肿瘤中约40%存在pRB缺陷，而另一组肿瘤中则没有pRB缺陷。细胞周期蛋白依赖性激酶抑制剂p16在44%的细胞周期蛋白E高表达且D1低表达的肿瘤中蛋白表达较高，这一结果支持了上述发现，并且所有免疫组化显示pRB缺陷的肿瘤均表现出较高的p16蛋白水平。此外，在所有免疫组化显示pRB缺陷的肿瘤中，除1例之外，均发现与高增殖活性和视网膜母细胞瘤易感基因位点杂合性缺失相关的异常低水平pRB磷酸化。有趣的是，细胞周期蛋白E高表达且D1低表达的肿瘤通常为雌激素受体阴性，这表明细胞周期调节因子在导致雌激素非依赖性肿瘤生长的机制中发挥作用。此外，不同组肿瘤患者的预后差异显著，这表明乳腺癌发病机制和临床病程的异质性在一定程度上可以由不同且独特的细胞周期缺陷组合来解释。
