Gene Amplifications Associated with the Development of Hormone-Resistant Prostate Cancer
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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 To whom requests for reprints should be addressed, at Endocrine Cancer Group, Surgical and Translational Research Section, Division of Cancer and Molecular Pathology, University Department of Surgery, Level II, Queen Elizabeth Building, Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom. Phone: 44-141-211-5436; Fax: 44-141-211-5432; E-mail: j.m.bartlett{at}clinmed.gla.ac.uk
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↵2 The abbreviations used are: AR, androgen receptor; PSA, prostate-specific antigen; PI3K, phosphatidylinositol 3′-kinase; MAPK, mitogen-activated protein kinase; CGH, comparative genomic hybridization; DOP, degenerate oligonucleotide primed; FISH, fluorescence in situ hybridization; RTK, Receptor tyrosine kinase; EGFR, epidermal growth factor receptor; FGF, fibroblast growth factor; TURP, transurethral resection of the prostate.
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↵3 J. Edwards, personal communication.
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- Accepted July 28, 1903.
- Received January 22, 1903.
- Revision received July 22, 1903.
