Ahlin Cecilia, Lundgren Claudia, Embretsén-Varro Elin, Jirström Karin, Blomqvist Carl, Fjällskog M -L
Department of Oncology, Örebro University, Örebro, Sweden.
Department of Immunology Genetics and Pathology (IGP), Uppsala University, Uppsala, Sweden.
Breast Cancer Res Treat. 2017 Aug;164(3):667-678. doi: 10.1007/s10549-017-4294-5. Epub 2017 May 20.
Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study.
Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression.
Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (ρ 0.19, p = 0.006) and B (ρ 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4).
We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.
细胞周期蛋白D1在细胞周期调控中起核心作用，是雌激素调节细胞周期进程的重要组成部分。我们之前已经表明，细胞周期蛋白D的高表达与雌激素受体阳性而非雌激素受体阴性乳腺癌的侵袭性特征相关。本研究的目的是验证这种与雌激素受体相关的差异效应，并在一项淋巴结阴性乳腺癌病例对照研究中进一步探讨细胞周期蛋白D过表达与CCND1基因扩增状态之间的关系。
对T1-2N0M0乳腺癌患者的组织微阵列切片进行细胞周期蛋白D1的免疫组织化学核表达检测（n = 364），并通过荧光原位杂交检测CCND1基因的扩增情况（n = 255）。排除接受辅助化疗的患者。主要事件定义为乳腺癌死亡。使用条件逻辑回归在单变量和多变量模型中分析乳腺癌特异性生存情况。
在雌激素受体阳性乳腺癌中，细胞周期蛋白D1表达高于中位数（61.7%）与乳腺癌死亡风险增加相关（比值比3.2，95%可信区间1.5 - 6.8），在调整肿瘤大小和分级后也是如此（比值比3.1）。在雌激素受体阴性病例中未发现细胞周期蛋白D1表达有显著的预后影响。在雌激素受体阳性肿瘤中，细胞周期蛋白D1过表达与增殖标志物细胞周期蛋白A（ρ 0.19，p = 0.006）和B（ρ 0.18，p = 0.003）的高表达显著相关，但在雌激素受体阴性病例中并非如此。CCND1扩增与细胞周期蛋白D1表达之间存在显著关联（p = 0.003），但CCND1扩增在统计学上没有显著的预后意义（风险比1.4，95%可信区间0.4 - 4.4）。
我们证实了之前的观察结果，即细胞周期蛋白D1高表达与雌激素受体阳性乳腺癌的高增殖以及乳腺癌死亡风险高三倍相关。
