The early effects of rapid androgen deprivation on human prostate cancer

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa).Therefore, understanding how ARs regulate the human transcriptome is of paramountimportance. The early effects of castration on human PCa have not previously beenstudied 27 patients medically castrated with degarelix 7 d before radical prostatec-tomy. We used mass spectrometry, immunohistochemistry, and gene expression array(validated by reverse transcription-polymerase chain reaction) to compare resectedtumour with matched, controlled, untreated PCa tissue. All patients had levels ofserum androgen, with reduced levels of intraprostatic androgen at prostatectomy.We observed differential expression of known androgen-regulated genes (TMPRSS2,KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upre-gulated following castration. AR regulation ofa-methylacyl-CoA racemase expressionand three other genes (FAM129A, RAB27A,andKIAA0101) was confirmed. Upregulationof oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia andwas associated with differential expression of ESR1-regulated genes and correlatedwith proliferation (Ki-67 expression).Patient summary:This first-in-man study defines the rapid gene expression changestaking place in prostate cancer (PCa) following castration. Expression levels of the genesthat the androgen receptor regulates are predictive of treatment outcome. Upregulationof oestrogen receptor 1 is a mechanism by which PCa cells may survive despitecastratio