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Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
Published on: November 2, 2013
Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays
L Bubendorf1, M Kolmer, J Kononen
1Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
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.
Insights
This study identifies key genes, including IGFBP2 and HSP27, overexpressed in hormone-refractory prostate cancer. These findings advance understanding of prostate cancer progression and potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer progression during hormonal therapy is poorly understood.
- Novel strategies are needed to identify genes involved in hormone-refractory prostate cancer.
Purpose of the Study:
- To identify differentially expressed genes in hormone-refractory prostate cancer.
- To develop a combined cDNA and tissue microarray approach for gene discovery.
Main Methods:
- cDNA microarray analysis of hormone-refractory (CWR22R) and hormone-sensitive (CWR22) prostate cancer xenografts.
- Tissue microarray construction and immunohistochemical analysis of clinical prostate cancer specimens.
Main Results:
- 37 genes showed >2-fold increased expression, and 135 genes showed >50% reduced expression in hormone-refractory xenografts.
- Insulin-like growth factor-binding protein 2 (IGFBP2) and heat-shock protein 27 (HSP27) were significantly overexpressed.
- IGFBP2 and HSP27 protein expression was high in hormone-refractory tumors compared to primary tumors and benign tissues.
Conclusions:
- Combined cDNA and tissue microarrays efficiently identify genes associated with prostate cancer progression.
- This approach facilitates the study of gene product roles in hormone-refractory prostate cancer pathogenesis.
