Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance.
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.
Holzbeierlein
Jeff
J
Department of Urology, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Lal
Priti
P
LaTulippe
Eva
E
Smith
Alex
A
Satagopan
Jaya
J
Zhang
Liying
L
Ryan
Charles
C
Smith
Steve
S
Scher
Howard
H
Scardino
Peter
P
Reuter
Victor
V
Gerald
William L
WL
D000465:Algorithms; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004359:Drug Therapy, Combination; D005485:Flutamide / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017273:Goserelin / Q000627:therapeutic use; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
D018931:Antineoplastic Agents, Hormonal; D017273:Goserelin; D005485:Flutamide