Barnes D M, Gillett C E
Hedley Atkins/ICRF Breast Pathology Laboratory, Guy's Hospital, London, UK.
Breast Cancer Res Treat. 1998;52(1-3):1-15. doi: 10.1023/a:1006103831990.
Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over-expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c-erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over-expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over-expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.
细胞周期蛋白D1在细胞周期的G1期调控细胞进程中发挥着重要作用。细胞周期蛋白D1基因（CCND1）在约20%的乳腺癌中发生扩增，其蛋白在约50%的病例中过度表达。这引发了人们对细胞周期蛋白D1是否为乳腺癌生物学标志物的深入研究；然而，临床研究却得出了意想不到的结果。对细胞系和转基因小鼠的研究表明，CCND1是一种弱癌基因，人们原本预计，与c-erbB-2一样，细胞周期蛋白D1蛋白的过度表达会与预后不良相关。早期的免疫组化预后研究结果不明确，但我们以及其他研究人员最近发现，细胞周期蛋白D1强染色更常见于高分化、雌激素受体阳性的癌组织中。此外，我们发现，无论从预后还是对内分泌治疗的反应来看，细胞周期蛋白D1的过度表达实际上与良好的预后相关。细胞周期蛋白D1在导管原位癌中经常过度表达，但在包括非典型导管增生在内的良性乳腺疾病中则不然；因此其表达似乎与致癌作用密切相关。为了帮助解释细胞周期蛋白D1过度表达的明显有益作用，人们还评估了一些密切相关的细胞周期蛋白，包括细胞周期蛋白依赖性激酶抑制剂p27，它可阻断细胞周期蛋白D1的激活作用。初步报告显示，高水平的p27与良好的预后相关，我们也发现p27与细胞周期蛋白D1表达之间呈正相关。细胞周期蛋白D1的这些临床研究结果表明，从基础细胞生物学研究中获得的信息需要通过临床研究来补充，以确定预后标志物的真正价值。
