Casimiro Mathew, Rodriguez Olga, Pootrakul Llana, Aventian Maral, Lushina Nadia, Cromelin Caroline, Ferzli Georgina, Johnson Kevin, Fricke Stanley, Diba Fantahun, Kallakury Bhaskar, Ohanyerenwa Chioma, Chen Maxine, Ostrowski Michael, Hung Mien-Chie, Rabbani Shafaat A, Datar Ram, Cote Richard, Pestell Richard, Albanese Chris
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Cancer Res. 2007 May 1;67(9):4364-72. doi: 10.1158/0008-5472.CAN-06-1898.
The receptor tyrosine kinase ErbB-2 plays an important role in the regulation of growth factor-induced signal transduction cascades in the epithelium, and ErbB-2 is frequently overexpressed in epithelial tumors. Our previous studies on clinical prostate cancer specimens indicated that ErbB-2 expression was increased in patients undergoing hormone ablation therapy. We had also shown that the critical cell cycle regulatory gene cyclin D1 and its promoter were targets of proliferative signaling in prostate cancer cell lines, and that cyclin D1 was required for ErbB-2-induced mammary tumorigenesis. In the current studies, we found that increased ErbB-2 membrane expression correlated with increased nuclear cyclin D1 staining in clinical prostate cancer specimens, and that expression of ErbB-2 was capable of inducing cell cycle progression in human prostate cancer cell lines. We further showed that ErbB-2 induced the cyclin D1 promoter in DU145 cells, and that small interfering RNA knockdown of cyclin D1 protein levels blocked a significant proportion of the heregulin-induced cell cycle progression in LNCaP cells. Probasin promoter-targeted expression of an activated ErbB-2 isoform induced cyclin D1 expression in the mouse prostate, commensurate with prostate intraepithelial neoplasia. Together, these in vitro and in vivo studies identify cyclin D1 as a critical downstream target of ErbB-2 in the prostate epithelium, both of which are possible therapeutic targets for cancer intervention. Furthermore, our novel mouse model provides a useful platform for ongoing in vivo investigations of ErbB-2 signaling in the prostate epithelium.
受体酪氨酸激酶ErbB-2在调节上皮细胞中生长因子诱导的信号转导级联反应中起重要作用，且ErbB-2在上皮肿瘤中常过度表达。我们之前对临床前列腺癌标本的研究表明，接受激素消融治疗的患者中ErbB-2表达增加。我们还表明，关键的细胞周期调节基因细胞周期蛋白D1及其启动子是前列腺癌细胞系中增殖信号的靶点，且细胞周期蛋白D1是ErbB-2诱导乳腺肿瘤发生所必需的。在当前研究中，我们发现临床前列腺癌标本中ErbB-2膜表达增加与细胞核细胞周期蛋白D1染色增加相关，且ErbB-2的表达能够诱导人前列腺癌细胞系中的细胞周期进程。我们进一步表明，ErbB-2在DU145细胞中诱导细胞周期蛋白D1启动子，且细胞周期蛋白D1蛋白水平的小干扰RNA敲低阻断了LNCaP细胞中相当一部分由这里格菌素诱导的细胞周期进程。前列腺素启动子靶向的活化ErbB-2异构体表达在小鼠前列腺中诱导细胞周期蛋白D1表达，与前列腺上皮内瘤变一致。总之，这些体外和体内研究确定细胞周期蛋白D1是前列腺上皮中ErbB-2的关键下游靶点，二者均可能是癌症干预的治疗靶点。此外，我们的新型小鼠模型为正在进行的前列腺上皮中ErbB-2信号传导的体内研究提供了一个有用的平台。
