Hui Rina, Finney Georgina L, Carroll Jason S, Lee Christine S L, Musgrove Elizabeth A, Sutherland Robert L
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales 2010, Australia.
Cancer Res. 2002 Dec 1;62(23):6916-23.
Cyclin D1 and cyclin E are overexpressed in approximately 45% and 30% of breast cancers, respectively, and adverse associations with patient outcome have been reported. The potential roles of cyclin D1 and cyclin E expression as markers of therapeutic responsiveness to the pure steroidal antiestrogen ICI 182780 were investigated using T-47D breast cancer cell lines constitutively overexpressing cyclin D1 or cyclin E. Measurement of S phase fraction, phosphorylation states of the retinoblastoma protein, and cyclin E-cyclin-dependent kinase (Cdk) 2 activity demonstrated that overexpression of cyclin D1 decreased sensitivity to antiestrogen inhibition at 24 and 48 h. Overexpression of cyclin E produced a less pronounced early cell cycle effect indicating only partial resistance to antiestrogen inhibition in the short-term. In ICI 182780-treated cyclin D1-overexpressing cells, sufficient Cdk activity was retained to allow retinoblastoma protein phosphorylation and cell proliferation, despite an increase in the association of p21 and p27 with cyclin D1-Cdk4/6 and cyclin E-Cdk2 complexes. After longer-term (>7 days) treatment, antiestrogens inhibited colony growth in cyclin D1- or cyclin E-overexpressing breast cancer cells, but with an approximately 2-2.5-fold decrease in dose sensitivity. This was associated with a fall in cyclin D1 levels, a reduction in the half-life of cyclin D1 protein and a decline in cyclin E-Cdk2 activity in cyclin D1-overexpressing cells, and the maintenance of cyclin E-p27 association in the cyclin E-overexpressing cells. These data confirm that cyclin D1 expression and cyclin E-p27 association play important roles in antiestrogen action, and suggest that cyclin D1 or cyclin E overexpression has subtle effects on antiestrogen sensitivity. Additional studies to elucidate the contribution of alterations in cyclin D1 stability to antiestrogen action and to assess the relationship between antiestrogen sensitivity and expression of cyclin D1, cyclin E, or p27 in a clinical setting are required.
细胞周期蛋白D1（Cyclin D1）和细胞周期蛋白E（Cyclin E）在大约45%和30%的乳腺癌中分别过表达，并且已有报道称它们与患者预后存在不良关联。使用持续过表达Cyclin D1或Cyclin E的T-47D乳腺癌细胞系，研究了Cyclin D1和Cyclin E表达作为对纯甾体类抗雌激素药物ICI 182780治疗反应性标志物的潜在作用。对S期比例、视网膜母细胞瘤蛋白的磷酸化状态以及Cyclin E - 细胞周期蛋白依赖性激酶（Cdk）2活性的测量表明，Cyclin D1的过表达在24小时和48小时时降低了对抗雌激素抑制的敏感性。Cyclin E的过表达产生的早期细胞周期效应不太明显，表明在短期内仅部分抵抗抗雌激素抑制。在经ICI 182780处理的过表达Cyclin D1的细胞中，尽管p21和p27与Cyclin D1 - Cdk4/6和Cyclin E - Cdk2复合物的结合增加，但仍保留了足够的Cdk活性以允许视网膜母细胞瘤蛋白磷酸化和细胞增殖。经过长期（>7天）治疗后，抗雌激素抑制了过表达Cyclin D1或Cyclin E的乳腺癌细胞中的集落生长，但剂量敏感性降低了约2 - 2.5倍。这与过表达Cyclin D1的细胞中Cyclin D1水平下降、Cyclin D1蛋白半衰期缩短以及Cyclin E - Cdk2活性降低相关，而过表达Cyclin E的细胞中Cyclin E - p27结合得以维持。这些数据证实Cyclin D1表达和Cyclin E - p27结合在抗雌激素作用中起重要作用，并表明Cyclin D1或Cyclin E过表达对抗雌激素敏感性有微妙影响。需要进一步研究以阐明Cyclin D1稳定性改变对抗雌激素作用的贡献，并评估临床环境中抗雌激素敏感性与Cyclin D1、Cyclin E或p27表达之间的关系。
