Königsberg Robert, Rögelsperger Olga, Jäger Walter, Thalhammer Theresia, Klimpfinger Martin, De Santis Maria, Hudec Marcus, Dittrich Christian
Third Medical Department, Centre for Oncology and Hematology, CEADDP, Applied Cancer Research, Institution for Translational Research Vienna, and Ludwig Boltzmann-Institute for Applied Cancer Research, Vienna, Austria.
Cancer Invest. 2008 Aug;26(7):734-40. doi: 10.1080/07357900801944864.
Cell cycle progression is regulated by cyclin dependent kinases (cdk) and cdk inhibitors. Recent immunohistological studies suggested that dysregulation of cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), and p27(kip1) are of prognostic value in patients with breast cancer. Our study represents the first comprehensive immunohistochemical cell cycle marker analysis for cdc25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb in tumor tissue and adjacent benign breast tissue from 69 primarily untreated breast cancer patients.
Immunhistochemistry using primary monoclonal antibodies to detect cdc 25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb has been performed.
Sixty-nine patients with untreated, invasive breast cancer (n = 69) were divided into a low/ intermediate and a high risk group according to the St. Gallen 2005 consensus conference. High risk patients (n = 22) had a significantly (p = 0.003) shorter mean and median survival (282.85 weeks; 383.0 weeks, respectively) than low/intermediate risk patients (375.41 weeks; not reached yet, respectively). A subgroup of high risk breast cancer patients characterized in addition by overexpression of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) experienced a shortened mean survival of 222.03, 235.71, 257.25, 239.18, and 261.94 weeks, respectively. Regarding benign breast tissue adjacent to breast cancer tissue, 59.4% of the patients investigated overexpressed cdc25A, 23.2% overexpressed pRb, and 63.2% exerted dysregulation of p27(kip1) while they proved to be negative for immunohistochemical staining regarding all other markers tested.
The immunohistological analyses of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) have the potential for further refining the risk assessment in patients with untreated breast cancer who belong to the high risk category defined according to the St. Gallen 2005 consensus conference. These cell cycle markers define a subgroup of high risk patients with even higher risk of metastazation and shortened survival. For confirmation a prospective study using standardized laboratory procedures in a larger population is needed.
细胞周期进程受细胞周期蛋白依赖性激酶（cdk）和cdk抑制剂调控。近期免疫组织学研究表明，细胞周期蛋白A、细胞周期蛋白D、细胞周期蛋白E、p16（ink4）、p21（waf1/cip1）和p27（kip1）的失调对乳腺癌患者具有预后价值。我们的研究首次对69例未经治疗的原发性乳腺癌患者的肿瘤组织及相邻乳腺良性组织中的细胞周期蛋白依赖性磷酸酶25A（cdc25A）、细胞周期蛋白A、细胞周期蛋白D、细胞周期蛋白E、p16（ink4）、p21（waf1/cip1）、p27（kip1）和视网膜母细胞瘤蛋白（pRb）进行了全面的免疫组织化学细胞周期标志物分析。
采用原发性单克隆抗体进行免疫组织化学检测，以检测cdc25A、细胞周期蛋白A、细胞周期蛋白D、细胞周期蛋白E、p16（ink4）、p21（waf1/cip1）、p27（kip1）和pRb。
根据2005年圣加仑共识会议，69例未经治疗的浸润性乳腺癌患者被分为低/中风险组和高风险组。高风险患者（n = 22）的平均生存期和中位生存期（分别为282.85周和383.0周）显著短于低/中风险患者（分别为375.41周和未达到）（p = 0.003）。另外，一组以cdc25A、细胞周期蛋白A、细胞周期蛋白E、p16（ink4a）和p27（kip1）过表达为特征的高风险乳腺癌患者，其平均生存期分别缩短至222.03周、235.71周、257.25周、239.18周和261.94周。对于乳腺癌组织相邻的乳腺良性组织，59.4%的受调查患者cdc25A过表达，23.2%的患者pRb过表达，63.2%的患者p27（kip1）失调，而在所有其他检测标志物的免疫组织化学染色中均为阴性。
对cdc25A、细胞周期蛋白A、细胞周期蛋白E、p16（ink4a）和p27（kip1）进行免疫组织学分析，有可能进一步完善对根据2005年圣加仑共识会议定义的高风险类别中未经治疗的乳腺癌患者的风险评估。这些细胞周期标志物定义了一个高风险患者亚组，其转移风险更高，生存期更短。为进行确证，需要在更大规模人群中采用标准化实验室程序开展一项前瞻性研究。
