Molecular endocrinology of target enzymes in androgen metabolism : Implications for prostate cancer

Sammanfattning: Genes that are responsible for variations in drug and hormonal responses are sometimes also associated with the pathophysiology of diseases. Understanding the aetiology of a disease is often essential for the design of effective drugs. Androgens are implicated in the development of prostate cancer and benign prostate hyperplasia (BPI]). This study aimed at characterising the therapeutic target enzymes steroid 5alpha-reductase 1 and 2 and the steroid metabolising enzyme cytochrome P450 1B I in relation to prostate cancer in order to gain a better view of the prostate tumor biology. The conversion of testosterone to the more potent metabolite dihydrotestosterone by steroid 5alpha-reductase 2 is a key mechanism in the action of androgens in the prostate. The 5alphareductase 2 specific messenger RNA (mRNA) levels were measured in 50 biopsies obtained from 31 Caucasian outpatients, using a solution hybridization method. Significant differences were observed between cancerous and noncancerous tissues. The median 5alpha- reductase 2 mRNA level in noncancerous tissue was 3.4 times higher than in cancerous specimens. 5alpha-reductase 2-specific gene expression and enzyme activity was further measured in 30 prostatic tissue specimens from 15 Caucasian patients. The enzyme activity at pH 5.5 was significantly correlated to the 5alpha-reductase 2-specific mRNA expression as measured by reverse-transcription PCR (RS=0.81). This association makes it possible to predict prostatic 5alpha-reductase 2 activity using core needle biopsies. In order to elucidate the role of 5alpha-reductase 2 polymorphisms, we performed a population based case control study in 176 Caucasian prostate cancer patients and 161 healthy controls of the importance of the V89L and A49T polymorphisms for the risk of prostate cancer, in relation to age and tumor characteristics. Carriers of the LL genotype were at increased risk of bone metastases at the time of diagnosis compared to the combined groups of individuals with VL or VV genotypes, OR 5.67 (95 % CI 1.44-22.30), when adjusted for age, differentiation grade, T-stage and PSA. Heterozygous prostate cancer cases carrying the AT genotype were significantly younger than cases harboring the AA genotype (mean age 66 vs 71 years). In the same patient material, the CYP1B1 V432L polymorphism was studied in relation to risk of prostate cancer and tumor characteristics. Carriers of the CYP1B1 432 LL genotype had a higher risk of metastases at the time of diagnosis compared to individuals with VL or VV genotypes, (OR 2.46, 95 % C.I 1.02-5.93) when adjusted for age, differentiation grade, Tstage and PSA. These findings may contribute to further understanding of the etiology of prostate cancer metastases.