Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance Journal Article

Authors: Holzbeierlein, J.; Lal, P.; LaTulippe, E.; Smith, A.; Satagopan, J.; Zhang, L.; Ryan, C.; Smith, S.; Scher, H.; Scardino, P.; Reuter, V.; Gerald, W. L.
Article Title: Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance
Abstract: The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.
Keywords: signal transduction; clinical article; controlled study; human tissue; treatment outcome; human cell; genetics; androgen; drug targeting; comparative study; genetic analysis; in situ hybridization, fluorescence; gene expression; gene expression profiling; drug effect; drug resistance; pathology; drug resistance, neoplasm; cell line, tumor; algorithms; cancer resistance; cancer hormone therapy; prostatic neoplasms; goserelin; gene expression regulation; gene expression regulation, neoplastic; fluorescence in situ hybridization; drug mechanism; drug combination; drug therapy, combination; algorithm; gene identification; nucleotide sequence; prostate tumor; tumor cell line; androgen receptor; upregulation; flutamide; antineoplastic agents, hormonal; antineoplastic hormone agonists and antagonists; prostate carcinoma; steroidogenesis; humans; human; male; priority journal; article
Journal Title: American Journal of Pathology
Volume: 164
Issue: 1
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2004-01-01
Start Page: 217
End Page: 227
Language: English
PROVIDER: scopus
PMCID: PMC1602218
PUBMED: 14695335
DOI: 10.1016/S0002-9440(10)63112-4
Notes: Am. J. Pathol. -- Cited By (since 1996):290 -- Export Date: 16 June 2014
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MSK Authors
  1. Jaya M Satagopan
    137 Satagopan
  2. Peter T Scardino
    621 Scardino
  3. Priti Lal
    34 Lal
  4. Charles Ryan
    9 Ryan
  5. Alexander D Smith
    28 Smith
  6. William L Gerald
    370 Gerald
  7. Liying Zhang
    89 Zhang
  8. Victor Reuter
    921 Reuter
  9. Howard Scher
    834 Scher
  10. Steven James Smith
    1 Smith