Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays.
BACKGROUND
The molecular mechanisms underlying the progression of prostate cancer during hormonal therapy have remained poorly understood. In this study, we developed a new strategy for the identification of differentially expressed genes in hormone-refractory human prostate cancer by use of a combination of complementary DNA (cDNA) and tissue microarray technologies.


METHODS
Differences in gene expression between hormone-refractory CWR22R prostate cancer xenografts (human prostate cancer transplanted into nude mice) and a xenograft of the parental, hormone-sensitive CWR22 strain were analyzed by use of cDNA microarray technology. To validate the data from cDNA microarrays on clinical prostate cancer specimens, a tissue microarray of specimens from 26 prostates with benign prostatic hyperplasia, 208 primary prostate cancers, and 30 hormone-refractory local recurrences was constructed and used for immunohistochemical detection of protein expression.


RESULTS
Among 5184 genes surveyed with cDNA microarray technology, expression of 37 (0.7%) was increased more than twofold in the hormone-refractory CWR22R xenografts compared with the CWR22 xenograft; expression of 135 (2.6%) genes was reduced by more than 50%. The genes encoding insulin-like growth factor-binding protein 2 (IGFBP2) and 27-kd heat-shock protein (HSP27) were among the most consistently overexpressed genes in the CWR22R tumors. Immunohistochemical analysis of tissue microarrays demonstrated high expression of IGFBP2 protein in 100% of the hormone-refractory clinical tumors, in 36% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P =.0001). Overexpression of HSP27 protein was demonstrated in 31% of the hormone-refractory tumors, in 5% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P =.0001).


CONCLUSIONS
The combination of cDNA and tissue microarray technologies enables rapid identification of genes associated with progression of prostate cancer to the hormone-refractory state and may facilitate analysis of the role of the encoded gene products in the pathogenesis of human prostate cancer.
Bubendorf
L
L
Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
Kolmer
M
M
Kononen
J
J
Koivisto
P
P
Mousses
S
S
Chen
Y
Y
Mahlamäki
E
E
Schraml
P
P
Moch
H
H
Willi
N
N
Elkahloun
A G
AG
Pretlow
T G
TG
Gasser
T C
TC
Mihatsch
M J
MJ
Sauter
G
G
Kallioniemi
O P
OP
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D018076:DNA, Complementary / Q000032:analysis / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000032:analysis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local; D011470:Prostatic Hyperplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D017211:Treatment Failure
D018931:Antineoplastic Agents, Hormonal; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D006360:Heat-Shock Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2