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(American Journal of Pathology. 2004;164:217-227.)
© 2004 American Society for Investigative Pathology

Gene Expression Analysis of Human Prostate Carcinoma during Hormonal Therapy Identifies Androgen-Responsive Genes and Mechanisms of Therapy Resistance

Jeff Holzbeierlein*, Priti Lal{dagger}, Eva LaTulippe{dagger}, Alex Smith{ddagger}, Jaya Satagopan{ddagger}, Liying Zhang{dagger}, Charles Ryan§, Steve Smith{dagger}, Howard Scher§, Peter Scardino*, Victor Reuter{dagger} and William L. Gerald{dagger}

From the Departments of Urology,* Pathology,{dagger} Epidemiology and Biostatistics,{ddagger} and the Department of Medicine,§ Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York; and the Department of Medicine, Joan and Sanford I. Weill College of Medicine of Cornell University, New York, New York

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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