Gene amplifications associated with the development of hormone- resistant prostate cancer

Edwards, J. , Krishnan, S., Witton, C.J. and Bartlett, J.M.S. (2003) Gene amplifications associated with the development of hormone- resistant prostate cancer. Clinical Cancer Research, 9(14), pp. 5271-5281.



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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 Amplione 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 greater than 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Edwards, Professor Joanne and Krishnan, Ms Sowmya
Authors: Edwards, J., Krishnan, S., Witton, C.J., and Bartlett, J.M.S.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RB Pathology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
Copyright Holders:Copyright © 2004 by the American Association for Cancer Research.
First Published:First published in Clinical Cancer Research 9(14):5271-5281
Publisher Policy:Reproduced with the permission of the Publisher.

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