Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance - PubMed (original) (raw)

Comparative Study

. 2004 Jan;164(1):217-27.

doi: 10.1016/S0002-9440(10)63112-4.

Priti Lal, Eva LaTulippe, Alex Smith, Jaya Satagopan, Liying Zhang, Charles Ryan, Steve Smith, Howard Scher, Peter Scardino, Victor Reuter, William L Gerald

Affiliations

Comparative Study

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

Jeff Holzbeierlein et al. Am J Pathol. 2004 Jan.

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.

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Figures

Figure 1

Figure 1

Representative microscopic images of prostate cancers used for expression analysis. A: Typical histological appearance of hormone therapy naive (untreated) prostate cancer. B: Typical histological appearance of prostate cancer after 3 months of neoadjuvant androgen ablation therapy (treated).

Figure 2

Figure 2

Average linkage hierarchical clustering dendrograms of samples demonstrating relationship of gene expression profiles based on all 12,559 probe sets of U95A array. A: Untreated primary (green) and androgen ablation-treated primary prostate cancers (yellow). B: Untreated primary and androgen ablation-treated primary prostate cancers and androgen ablation-resistant metastatic prostate cancers (pink).

Figure 3

Figure 3

AR expression in human prostate cancers. A: Bar graph representing AR transcript levels based on hybridization of cDNA target to oligonucleotide arrays. Two different probe sets for AR are presented. B and C: Immunohistochemical detection of the AR in representative primary untreated prostate cancer with low level of AR transcripts (B) and metastatic AARPC with high levels (C). D and E: Fluorescent in situ hybridization for AR (red) and chromosome X centromere (green) in metastatic AARPC with high levels of AR transcripts and no amplification of the AR gene (D) and metastatic AARPC with high level of AR expression and AR amplification (E).

Figure 4

Figure 4

Schematic diagram of steroid biosynthesis with superimposed gene expression changes in androgen ablation-resistant prostate cancer.

Figure 5

Figure 5

Immunohistochemical detection of squalene monooxygenase in prostate cancer samples. Liver serves as positive control.

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