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.