ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo.
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.
Casimiro
Mathew
M
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Rodriguez
Olga
O
Pootrakul
Llana
L
Aventian
Maral
M
Lushina
Nadia
N
Cromelin
Caroline
C
Ferzli
Georgina
G
Johnson
Kevin
K
Fricke
Stanley
S
Diba
Fantahun
F
Kallakury
Bhaskar
B
Ohanyerenwa
Chioma
C
Chen
Maxine
M
Ostrowski
Michael
M
Hung
Mien-Chie
MC
Rabbani
Shafaat A
SA
Datar
Ram
R
Cote
Richard
R
Pestell
Richard
R
Albanese
Chris
C
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D019940:Genes, bcl-1; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*
D019938:Cyclin D1; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases