Westbrook Louise, Ramanathan Harish N, Isayeva Tatyana, Mittal Anshu Roy, Qu Zhican, Johnson Michael D, Kern Francis G, Ponnazhagan Selvarangan, Grubbs Clinton J, Thottassery Jaideep V
Biochemistry and Molecular Biology Department, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35255, USA.
Int J Oncol. 2009 May;34(5):1425-31.
Cks1 plays an essential role in SCFSkp2-mediated ubiquitination, and consequently turnover, of the cdk2 inhibitor and tumor supressor p27Kip1. High Cks1 expression is associated with aggressive breast tumors and correlates with low p27Kip1 levels in some cases, although it is also an independent prognostic marker for survival, and provides predictive information in addition to that provided by p27Kip1 alone. In this report we demonstrate that Cks1 protein and mRNA are elevated to very high levels in mammary tumors initiated by erbB2, c-myc and polyoma middle-T (PyMT) in transgenic mice, whereas Cks1 protein is hardly detectable in the normal mammary epithelium. Cks1 is also highly upregulated in rat mammary tumors initiated by methylnitrosourea (MNU). Despite high levels of Cks1 expression, p27Kip1 levels were not reduced, and were in fact slightly higher in mammary tumors initiated by erbB2, PyMT and MNU. In contrast mammary tumors from MMTV-c-myc mice did exhibit low p27Kip1 and higher levels of Skp2. Together, these data suggest that deregulated Cks1 expression might play roles in oncogene and carcinogen-initiated mammary tumorigenesis independent of p27Kip1 turnover in certain tumors. Stable overexpression of Cks1 in human breast carcinoma MCF-7 cells did not significantly reduce p27Kip1 expression, although it conferred resistance to Faslodex (ICI 182780)-mediated inhibition of colony outgrowth in these cells. In contrast, Cks1-depleted MCF-7 cells formed fewer colonies in estrogen-containing medium. Therefore, our studies also suggest that Cks1 levels regulate the responsiveness of ER+ breast cancers to estrogens and anti-estrogens.
Cks1在SCFSkp2介导的细胞周期蛋白依赖性激酶2（cdk2）抑制剂及肿瘤抑制因子p27Kip1的泛素化过程中发挥着重要作用，进而影响其周转。Cks1高表达与侵袭性乳腺癌相关，在某些情况下与低水平的p27Kip1相关，尽管它也是生存的独立预后标志物，并且除了单独的p27Kip1所提供的信息外还能提供预测信息。在本报告中，我们证明在转基因小鼠中由erbB2、c-myc和多瘤病毒中T抗原（PyMT）引发的乳腺肿瘤中，Cks1蛋白和mRNA水平升高至非常高的水平，而在正常乳腺上皮中几乎检测不到Cks1蛋白。在由甲基亚硝基脲（MNU）引发的大鼠乳腺肿瘤中，Cks1也高度上调。尽管Cks1表达水平很高，但在由erbB2、PyMT和MNU引发的乳腺肿瘤中，p27Kip1水平并未降低，实际上反而略高。相比之下，来自MMTV-c-myc小鼠的乳腺肿瘤确实表现出低水平的p27Kip1和更高水平的Skp2。总之，这些数据表明，在某些肿瘤中，Cks1表达失调可能在癌基因和致癌物引发的乳腺肿瘤发生中发挥作用，而与p27Kip1的周转无关。在人乳腺癌MCF-7细胞中稳定过表达Cks1并没有显著降低p27Kip1的表达，尽管它赋予了这些细胞对氟维司群（ICI 182780）介导的集落生长抑制的抗性。相反，Cks1缺失的MCF-7细胞在含雌激素的培养基中形成的集落较少。因此，我们的研究还表明，Cks1水平调节雌激素受体阳性（ER+）乳腺癌对雌激素和抗雌激素的反应性。
