ErbB-2 Induces the Cyclin D1 Gene in Prostate Epithelial Cells In vitro and In vivo

Abstract

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. [Cancer Res 2007;67(9):4364-72]

A Reduction in Pten Tumor Suppressor Activity Promotes ErbB-2-Induced Mouse Prostate Adenocarcinoma Formation through the Activation of Signaling Cascades Downstream of PDK1

“…3,17 Briefly the minimal rat probasin promoter was used to drive prostate-specific expression of an activated ErbB-2 growth factor receptor. 3,17 The pten ϩ/Ϫ mice, which harbor hemizygous inactivation of one pten allele and PB-CRE ϫ Pten PC1 mice, which delete both pten alleles in the prostate epithelium as previously reported 13,18 were kindly provided by Dr. Pier Paolo Pandolfi, Memorial Sloan-Kettering Cancer Center/Beth Israel Deaconess Medical Center. The compound-engineered PB-ErbB-2 ϫ pten ϩ/Ϫ mice in an FVBN background resulted from the repeated cross-breeding of the Pten ϩ/Ϫ mice into the PB-ErbB-2 line for six or more generations.…”

“…1,2 In previous studies, we established that increased ErbB-2 membrane expression correlated with increased nuclear cyclin D1 staining in clinical PCa specimens. 3 We also established in human PCa cell lines that ErbB-2 induced both cell cycle proliferation and cyclin D1, and that small interfering RNA targeting cyclin D1 blocked a significant proportion of the ErbB-2 or heregulin-induced cell cycle progression. Furthermore, we established that probasin-driven ErbB-2 transgene mice (PB-ErbB-2) presented with high-grade prostate intraepithelial neoplasia, (PIN), a localized adenoma, and induced epithelial cyclin D1 expression; transformation to adenocarcinoma was not observed.…”

“…1,2 In previous studies, we established that increased ErbB-2 membrane expression correlated with increased nuclear cyclin D1 staining in clinical PCa specimens. 3 We also established in human PCa cell lines that ErbB-2 induced both cell cycle proliferation and cyclin D1, and that small interfering RNA …”

“…Furthermore, we established that probasin-driven ErbB-2 transgene mice (PB-ErbB-2) presented with high-grade prostate intraepithelial neoplasia, (PIN), a localized adenoma, and induced epithelial cyclin D1 expression; transformation to adenocarcinoma was not observed. 3 The phosphatidylinositol-3-kinase (PI3K) signaling pathway is a major mediator of receptor tyrosine kinase signaling and plays an important role in controlling cell proliferation and cell survival. Pten is a lipid phosphatase that catalyzes the dephosphorylation of phosphatidylinositol-3,4,5-tri-phosphate and phosphatidylinositol-3,4-bis-phosphate, thereby inhibiting PI3K signaling.…”

Lactate dehydrogenase, Gleason score and HER-2 overexpression are significant prognostic factors for M1b prostate cancer

“…It stimulates cell differentiation and proliferation through the ligand binding to the extracellular domain. Some recent studies indicated that HER-2 stimulates AKT pathway or cyclin D1 and prolongs life or activates growth of PC cells, inhibiting apoptosis (28)(29)(30).…”