Abstract
Levels of enzymes that determine testosterone catabolism such as CYP3A4 have been associated with prostate cancer (PCa) risk. Although some studies have related CYP3A4*1B allele, a gene polymorphism that modifies CYP3A4 expression level, with PCa risk, others have failed, suggesting that additional genetic variants may be involved. Expression of CYP3A4 is largely due to the activation of Pregnane X Receptor (PXR). Particularly, rs2472677 and rs7643645 PXR polymorphisms modify CYP3A4 expression levels. To evaluate whether PXR-HNF3β/T (rs2472677), PXR-HNF4/G (rs7643645), and CYP3A4*1B (rs2740574) polymorphisms are associated with PCa a case control-study was performed. The multiple testing analysis showed that the PXR-HNF4/G polymorphism was associated with higher levels of prostate-specific antigen (PSA) in patients with PCa (OR = 3.99, p = 0.03). This association was stronger in patients diagnosed at the age of 65 years or older (OR = 10.8, p = 0.006). Although the CYP3A4*1B/*1B genotype was overrepresented in PCa patients, no differences were observed in the frequency of this and PXR-HNF3β/T alleles between controls and cases. Moreover, no significant association was found between these polymorphisms and PSA, Gleason grade, or tumor lymph node metastasis.
Highlights
Prostate cancer (PCa) is the second most common cancer worldwide in males and one of the most common causes of death in men (IARC, 2008)
In the present case-control study, we investigated whether CYP3A4*1B variant was associated with several clinic characteristics of prostate cancer
The CYP3A4*1B variant was not in Hardy-Weinberg equilibrium (HWE) in the case group most likely due to the excess of homozygous CYP3A4*1B genotype presented in this group
Summary
Prostate cancer (PCa) is the second most common cancer worldwide in males and one of the most common causes of death in men (IARC, 2008). It has been established that steroid hormone levels, in particular androgens, affect the risk of developing PCa [3,4]. Testosterone and predominantly its metabolite dihydrotestosterone interact with the androgen receptor, which leads to the expression of genes involved in the growth of the prostate and the proliferation of prostate cancer cells [5]. It has been hypothesized that low levels and/or decreased CYP3A4 activity might result in a lower capacity to inactivate testosterone favoring its conversion to dihydrotestosterone and increasing the risk of developing PCa. decreased expression of CYP3A4 has been found in prostatic tissues from PCa patients compared to 93% for benign epithelium, and only 75% of prostate tumors expressed CYP3A4 [10]
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