Hormonal Oncogenesis Laboratory, University of Kansas Cancer Center, Kansas, KS 66160, USA.
Horm Cancer. 2010 Feb;1(1):34-43. doi: 10.1007/s12672-009-0004-z. Epub 2010 Feb 10.
Overexpressed Aurora A, amplified centrosomes, and aneuploidy are salient features of estrogen-induced mammary preinvasive lesions and tumors in female August--Copenhagen Irish (ACI) rats. Intimately involved in these events are cyclins and their associated cyclin-dependent kinase (CDK) partners. Cyclin E1·CDK2 overexpression plays an important dual role in late G1/S phase of the cell cycle in cancer cells. It increases DNA replication providing growth advantage to cancer cells and facilitates aberrant centrosome duplication, generating chromosomal instability and aneuploidy leading to tumor development. Presented herein, a 24.0- and 45.0-fold elevation in cyclin E1 and CDK2 was found in 17β-estradiol (E(2))-induced ACI rat mammary tumors (MTs), respectively. Cyclin E·CDK2 positive staining was confined to the large round cells found within focal dysplasias, ductal carcinomas in situ, and invasive MTs. Co-immunoprecipitation and in vitro kinase activity of these tumors revealed that these cell cycle entities are functional. When mammary tissue derived from untreated normal, E(2)-induced hyperplasia and primary tumors were normalized to cyclin E1 levels, low molecular weight (LMW) cyclin E1 forms (33- and 45-kDa) were detected in all of these tissue groups. Moreover, increasing concentrations of protease inhibitor in tissue lysates resulted in a marked reduction of LMW forms, indicating that the presence of cyclin E1 LMW forms can be markedly reduced. Significant increases in cyclin E1 mRNA (2.1-fold) were detected in primary ACI rat E(2)-induced breast tumors, and quantitative real-time polymerase chain reaction revealed a 20% amplification of the cyclin E1 gene (CCNE1). Collectively, these results support the involvement of cyclin E1·CDK2 in centrosome overduplication during each stage of E(2)-induced mammary tumorigenesis.
过表达的 Aurora A、扩增的中心体和非整倍性是雌激素诱导的雌性 August--Copenhagen Irish（ACI）大鼠乳腺前浸润性病变和肿瘤的显著特征。细胞周期蛋白及其相关的细胞周期蛋白依赖性激酶（CDK）伴侣密切参与这些事件。细胞周期蛋白 E1·CDK2 过表达在癌细胞的细胞周期晚期 G1/S 期发挥着重要的双重作用。它增加了 DNA 复制，为癌细胞提供了生长优势，并促进了异常中心体复制，导致染色体不稳定和非整倍体，从而导致肿瘤的发展。本文报道，在 17β-雌二醇（E2）诱导的 ACI 大鼠乳腺肿瘤（MT）中，细胞周期蛋白 E1 和 CDK2 的表达分别升高了 24.0 倍和 45.0 倍。细胞周期蛋白 E·CDK2 阳性染色仅限于局灶性发育不良、原位导管癌和浸润性 MT 中发现的大圆形细胞。这些肿瘤的共免疫沉淀和体外激酶活性表明这些细胞周期实体是功能性的。当来自未处理的正常、E2 诱导的增生和原发性肿瘤的乳腺组织按细胞周期蛋白 E1 水平归一化时，所有这些组织群体中都检测到低分子量（LMW）细胞周期蛋白 E1 形式（33-和 45-kDa）。此外，组织裂解物中蛋白酶抑制剂浓度的增加导致 LMW 形式的明显减少，表明细胞周期蛋白 E1 LMW 形式的存在可以明显减少。在原发性 ACI 大鼠 E2 诱导的乳腺癌中，细胞周期蛋白 E1 mRNA 显著增加（2.1 倍），实时定量聚合酶链反应显示细胞周期蛋白 E1 基因（CCNE1）扩增 20%。综上所述，这些结果支持细胞周期蛋白 E1·CDK2 参与了 E2 诱导的乳腺肿瘤发生过程中每个阶段的中心体过度复制。
