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Clinical Cancer Research
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Gene Amplifications Associated with the Development of Hormone-Resistant Prostate Cancer

Joanne Edwards, N. Sarath Krishna, Caroline J. Witton and John M. S. Bartlett
Joanne Edwards
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N. Sarath Krishna
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Caroline J. Witton
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John M. S. Bartlett
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DOI:  Published November 2003
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Abstract

Purpose: Hormone resistance remains a significant clinical problem in prostate cancer with few therapeutic options. Research into mechanisms of hormone resistance is essential.

Experimental Design: We analyzed 38 paired (prehormone/posthormone resistance) prostate cancer samples using the Vysis GenoSensor. Archival microdissected tumor DNA was extracted, amplified, labeled, and hybridized to Amplionc I DNA microarrays containing 57 oncogenes.

Results: Genetic instability increased during progression from hormone-sensitive to hormone-resistant cancer (P = 0.008). Amplification frequencies of 15 genes (TERC, MYBL3, HRAS, PI3KCA, JUNB, LAMC2, RAF1, MYC, GARP, SAS, FGFR1, PGY1, MYCL1, MYB, FGR) increased by >10% during hormone escape. Receptor tyrosine kinases were amplified in 73% of cases; this was unrelated to development of hormone resistance. However, downstream receptor tyrosine kinase signaling pathways showed increased amplification rates in resistant tumors for the mitogen-activated protein kinase (FGR/Src-2, HRAS, and RAF1; P = 0.005) and phosphatidylinositol 3′-kinase pathways (FGR/Src-2, PI3K, and Akt; P = 0.046). Transcription factors regulated by these pathways were also more frequently amplified after escape (MYC family: 21% before versus 63% after, P = 0.027; MYB family: 26% before versus 53% after, P = 0.18).

Conclusions: Development of clinical hormone escape is linked to phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways. These pathways may function independently of the androgen receptor or via androgen receptor activation by phosphorylation, providing novel therapeutic targets.

  • Received January 22, 2003.
  • Revision received July 22, 2003.
  • Accepted July 28, 2003.
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Clinical Cancer Research: 9 (14)
November 2003
Volume 9, Issue 14
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Gene Amplifications Associated with the Development of Hormone-Resistant Prostate Cancer
Joanne Edwards, N. Sarath Krishna, Caroline J. Witton and John M. S. Bartlett
Clin Cancer Res November 1 2003 (9) (14) 5271-5281;

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Gene Amplifications Associated with the Development of Hormone-Resistant Prostate Cancer
Joanne Edwards, N. Sarath Krishna, Caroline J. Witton and John M. S. Bartlett
Clin Cancer Res November 1 2003 (9) (14) 5271-5281;
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Clinical Cancer Research
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