Expression profiling of the mouse prostate after castration and hormone replacement: implication of H-cadherin in prostate tumorigenesis.
Mice have been used extensively for studying normal prostate development and for generation of transgenic or knock-out prostate cancer animal models. To understand systematically and thoroughly the androgen responsive program in the mouse prostate, we carried out microarray analysis to profile gene expression changes during prostate involution and re-growth triggered by castration and subsequent hormone replacement. Genes with significant changes in these two processes were identified and gene ontology analyses revealed that they were mainly involved in response mechanisms, cell adhesion, metabolism, protein metabolism, and cell-cycle progression. The changes observed during prostate involution were largely reversed during re-growth. Sixty-four genes, including Nkx3.1 and probasin, and 65 other genes, including insulin-like growth factor binding protein 3 and H-cadherin (H-Cad), were further identified respectively as androgen-responsive genes and genes inversely correlated with androgen, based on their down- or up-regulation following castration and up- or down-regulation following androgen replacement. Potential androgen-responsive elements were found in the 5' upstream promoter region of 47 of those 65 genes, suggesting a potential suppression mechanism by androgen receptor. Of these, the role of H-Cad in tumorigenesis was further evaluated. Reduction of H-Cad transcript level was found in the majority of human prostate cancer cell lines and prostatic adenocarcinoma samples examined. Furthermore, induced H-Cad expression in DU145 cells, and knock-down of H-Cad expression in BPH1 cells inhibited and facilitated tumorigenicity, respectively. Taken together, our study provides a molecular understanding of the mouse prostate involution and re-growth processes and identifies a set of genes that are inversely correlated with androgen and may be potentially suppressive for tumorigenesis.
Wang
Xi-De
XD
Department of Molecular Biology, MS 72, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Wang
Bu-Er
BE
Soriano
Robert
R
Zha
Jiping
J
Zhang
Zemin
Z
Modrusan
Zora
Z
Cunha
Gerald R
GR
Gao
Wei-Qiang
WQ
D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002369:Castration; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000209:etiology / Q000378:metabolism*; D015854:Up-Regulation
D000728:Androgens; D015820:Cadherins; C099972:H-cadherin