Microarray analysis of prostate cancer progression to reduced androgen dependence: Studies in unique models contrasts early and late molecular events Journal Article
| Authors: | Sirotnak, F. M.; She, Y.; Khokhar, N. Z.; Hayes, P.; Gerald, W.; Scher, H. I. |
| Article Title: | Microarray analysis of prostate cancer progression to reduced androgen dependence: Studies in unique models contrasts early and late molecular events |
| Abstract: | Three unique variants of the CWR22 human prostate cancer xenograft model (CWR22LD1, LD2, and LD3) with a decrease in dependence on androgens were selected under noncastrate conditions, i.e., by outgrowth after transplantation into male NCR (AT) nu mice without testosterone supplementation. These variants were unable to grow in castrated male mice. For comparison, a second set of variants with even less dependence on androgens (castrate-resistant) were derived following outgrowth from CWR22 (CWR22Rv1 and RC) or CWRLD1 (CWR22RS) after transplantion in castrated male mice. The androgen receptor (AR) gene in the CWR22LD variants was transcriptionally active and was neither mutated nor significantly overexpressed compared to CWR22. Oligonucleotide microarray analysis showed distinctly different profiles of dysregulated gene expression among the CWR22LD variants. Groups of only 26-41 genes were dysregulated greater than threefold with a different proportion of up versus downregulated genes in each variant. Only one of the castrate-resistant variants (CWR22Rv1) had a highly overexpressed AR gene but AR in this variant and the two other castrate-resistant variants, CWR22 RS and RC, was not mutated beyond that seen in CWR22. In contrast to the CWR22LD variants, a total of 342, 295, and 222 genes were dysregulated at least threefold in CWR22Rv1, CWR22RS, and CWR22RC, respectively, differing as well in the proportion of up versus downregulated genes. Many of the genes dysregulated in CWR22LD1, LD2, and LD3 were further dysregulated in CWR22Rv1, RC, or RS. The most downregulated gene was microseminoprotein beta (MSPB). Along with cyclin D1, the most upregulated gene by an order of magnitude compared to other upregulated genes was hepatocyte growth factor (HGF) (scatter factor). These results suggest that the onset in the loss of androgen dependence in CWR22 proceeds through multiple pathways and does not require any direct change in the status of AR. However, upregulation of other survival pathways like that involving HGF in these studies could co-activate AR signaling. The endogenous overexpression of genes regulating sterol biosynthesis also observed in castrate-resistant CWR22 variants delineated a clinically relevant, compensatory mechanism for overcoming androgen deprivation reaffirming a central role for AR signaling in this process. © 2004 Wiley-Liss, Inc. |
| Keywords: | signal transduction; controlled study; gene mutation; androgen; nonhuman; mouse; animals; mice; animal tissue; gene overexpression; gene expression profiling; transcription initiation; neoplasm proteins; prostate cancer; prostatic neoplasms; models, animal; scatter factor; gene expression regulation; gene expression regulation, neoplastic; xenograft; nude mouse; mice, nude; reverse transcriptase polymerase chain reaction; oligonucleotide array sequence analysis; disease progression; nucleotide sequence; transplantation, heterologous; gene control; down regulation; dna microarray; castration; molecular biology; cyclin d1; unindexed sequence; androgens; neoplasms, hormone-dependent; hgf; trixis; humans; male; priority journal; article; androgen-independent prostate cancer; cwr22 microarray |
| Journal Title: | Molecular Carcinogenesis |
| Volume: | 41 |
| Issue: | 3 |
| ISSN: | 0899-1987 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2004-11-01 |
| Start Page: | 150 |
| End Page: | 163 |
| Language: | English |
| DOI: | 10.1002/mc.20051 |
| PROVIDER: | scopus |
| PUBMED: | 15390081 |
| DOI/URL: | |
| Notes: | Mol. Carcinog. -- Cited By (since 1996):27 -- Export Date: 16 June 2014 -- CODEN: MOCAE -- Molecular Sequence Numbers: GENBANK: AA551075, AA654586, AB002384, AB059408, AF088867, AF130095, AF288391, AI189753, AI634532, AI691323, AI718937, AJ276395, AK022172, AK026737, AL524520, AL533838, AU144165, BC000055, BC001012, BC005035, BC005858, BC005939, BF338947, BF342851, BF347089, D86983, D90427, M73554, M90657, NM_000503, NM_000735, NM_000905, NM_001141, NM_001814, NM_002851, NM_003070, NM_003308, NM_004056, NM_004116, NM_004502, NM_005059, NM_005239, NM_005635, NM_019058, NM_020142, NM_022765, NM_025190, W80357, X02761, X15306; -- Source: Scopus |
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