Early upregulation of AR and steroidogenesis enzyme expression after 3 months of androgen-deprivation therapy

Abstract

Background: Androgen deprivation therapy (ADT) is a standard treatment for advanced prostate cancer (PCa). However, PCa recurrence and progression rates during ADT are high. Until now, there has been no evidence regarding when progression begins. This study evaluated the gene expression of intraprostatic androgen receptor (AR) and steroidogenic enzymes in the early stages of ADT. Methods: Prostate tissue samples were taken from PCa patients with urinary retention who received ADT (ADT-PCa; n = 10) and were further subgrouped into ADT ≤12 months (n = 4) and ADT > 12 months (n = 6). The ADT-PCa tissues were then compared with BPH (n = 12) and primary (no treatment) PCa tissues (n = 16). mRNA for gene expression analysis of AR and steroidogenic enzymes was extracted from formalin-fixed paraffin embedded (FFPE) tissues and analyzed by real-time PCR. Protein expression was evaluated by immunohistochemistry with specific antibodies. Results: AR gene expression was higher in the ADT-PCa group than in the BPH or primary PCa group. Both the ADT ≤12 and > 12 months subgroups had significantly higher relative gene expression levels of AR (p < 0.01 and 0.03, respectively) than the primary PCa group. In the ADT-PCa group, AR protein expression showed an increasing trend in the ADT ≤12 months subgroup and was significantly elevated in the ADT > 12 months subgroup compared with the PCa group (100%; p < 0.01). Half (50%) of the patients in the ADT ≤12 months subgroup were found to have upregulation of AR, and one showed upregulation beginning at 3 months of ADT. A trend toward elevated relative gene expression of SRD5A3 was also apparent in the ADT groups. Conclusion: AR and steroidogenic enzymes are upregulated in ADT-PCa patients as early as 3 months, without PSA elevation. Steroidogenic enzymes, particularly SRD5A3, were also upregulated before PSA rose.

KLK3 SNP–SNP interactions for prediction of prostate cancer aggressiveness

“…SRD5A2 converts testosterone to dihydrotestosterone, which activates ARs 53,54 . SRD5A2 expression was significantly higher among patients with high-grade PCa vs. those with low-grade PCa 55,56 . In our previous study, we reported that the validated SNP-SNP interaction pairs of MMP16-EGFR, MMP16-ROBO1, and MMP16-CSF1 were significantly associated with PCa aggressiveness and that EGFR is the hub of these interactions 13 .…”

Stroma biglycan expression can be a prognostic factor in prostate cancers

“…However, in this study, there was no relationship between BGN expression and AR status (Figure S2). Furthermore, AR is known to be mutated by hormone therapy 27,28 . Thus, the AR may have been mutated during hormone therapy, but we were unable to determine whether the AR in the cases were mutated or not.…”

PSSD,PFS,PRSD: A perspective for aetiology and treatment

“…Variations in hormonal levels provoke adaptations in expression and activity of Estrogen and Androgen Receptors [86,87,88,89,90,91]. Estrogen deprivation has been shown to lead to ER oversensitisation, whereas constant activation of ERs to desensitisation [88,90].…”

“…The mechanisms behind the adaptations Similar reorganisation is known to occur after changes in the hormonal environment through other pathways. The removal of the gonads, perinatal exposure to sex hormones and the hormonal increases during puberty, all cause an abruptly altered hormonal environment, which subsequently leads to changes in receptor expression [84,86,87]. For example, pubertal emergence of sexual behaviour is induced by increased gonadal production and accompanied by synaptic reorganisation of the amygdala.…”