Codon 89 polymorphism in the human 5 α -reductase gene in primary breast cancer

Abstract

SummaryThe enzyme human steroid 5-α reductase type II (SRD5A2) and androgen receptor (AR) are critical mediators of androgen action, suggesting a potential role in hormonally related cancers. The SRD5A2 gene harbours two frequent polymorphic sites, one in the coding region, at codon 89 of exon 1, where valine is substituted by leucine (V89L) and the other in the 3′ untranslated region (3′ UTR) where a variable number of dinucleotide TA repeat lengths exists. The V89L polymorphism is known to alter the activity of this enzyme. In the present study we examined 144 sporadic breast tumours from Italian patients for the V89L and TA polymorphisms by sequence and fragment analysis, respectively. Tumour extract prostate specific antigen (PSA) concentration as well as a number of well-established clinical and pathological parameters were evaluated. The results show that 53% of the tumours were homozygous for VV alleles, 37% were heterozygous for VL alleles and 10% were homozygous for LL alleles. TA(0) repeats were found in tumours with VV, LL and VL genotypes. TA(9) repeats were only found in VV homozygotes and were totally absent from either LL homozygotes or VL heterozygotes. PSA expression was significantly elevated in tumours with VV genotype. The presence of LL alleles in breast tumours is associated with earlier onset and shorter disease-free (RR = 2.65; P = 0.013) and overall survival (RR = 3.06; P = 0.014) rates. The VV genotype is associated with a more favourable prognosis. Our study suggests that the polymorphism in codon 89 of exon 1 of the human 5α-reductase gene is related with TA repeat genotypes, PSA expression and breast cancer prognosis. More specifically, we found that the LL genotype is also associated with earlier onset and more aggressive forms of breast cancer. Long-term-outcome studies are needed to investigate the relevance of this polymorphism to breast cancer susceptibility. substitution (A49T) along with the variable length dinucleotide TA repeats on the 3′ untranslated region of this gene occur sufficiently frequently in the population to be considered as gene polymorphisms (Vilchis et al, 1997). These alterations are capable of affecting the incidence of prostate cancer (Reichardt et al, 1995). These 2 single nucleotide changes as well as other mutations, as shown by site-directed mutagenesis, impair the reductase activity in one way or the other (Wigley et al, 1994;Makridakis et al, 1997;Makridakis et al, 2000). Decrease in the activity of this enzyme in prostate cancer has been linked to favourable prognosis (Kantoff et al, 1997). The decrease in prostate volume and PSA level in men treated with the reductase inhibitor finasteride, lends more credence to this idea (Gormley et al, 1992;Magklara et al, 1999Magklara et al, , 2000. No data is available on the role of this enzyme in breast cancer. In prostate cancer, the homozygote VV genotype of the V89L polymorphism has been associated with high reductase activity and high DHT levels. The homozygote LL genotype has been associated with low re...

Associations between the SRD5A2 gene V89L and TA repeat polymorphisms and breast cancer risk: a meta-analysis

“…Certain other limitations of our meta-analysis also need to be acknowledged. First, some high-quality studies were excluded owing to a lack of raw data (Scorilas et al, 2001). Furthermore, the studies could not exclude latent breast cancer in the controls, who might have had different risks for developing breast cancer.…”

Complexities of androgen receptor signalling in breast cancer

“…This effect on prognosis may be due to androgen regulation of steroid intracrinology, indicating the need for a better understanding of androgen intracrinology to better define the role of AR in breast tumourigenesis. Polymorphisms in the 5aR2 gene that decrease enzyme activity, and therefore reduce DHT levels, are associated with an increased breast cancer risk (Francis et al 2014) and/or shorter survival (Bharaj et al 2000, Scorilas et al 2001, although significant harmful effects of these alleles have not been consistently reported (Spurdle et al 2001, Yang et al 2002, van Gils et al 2003. Increased levels of 5aR2, but not 5aR1, were detected in ERa-positive breast tumours in which the proliferation index decreased by more than 40% following aromatase inhibitor therapy (Chanplakorn et al 2011).…”

Adiposity, estradiol, and genetic variants of steroid-metabolizing enzymes as determinants of bone mineral density

“…This gene codes for 5a-reductase type II, the enzyme converting testosterone into the active compound dihydrotestosterone. We studied a G/C non-synonymous polymorphism at codon 89 (V89L), which has been associated to serum sex steroids and hormone-dependent cancers in some studies (6)(7)(8).…”

“…We planned this study to explore the influence of several anthropometric, lifestyle, genetic, and hormonal factors on BMD and analyze the possible differences in men and women. In particular, we decided to study three polymorphisms of genes coding for enzymes involved in the metabolism of sex steroids which have been previously found associated to certain hormonesensitive conditions, namely 17-hydroxylase, 5a-reductase, and sulfotransferase (4)(5)(6)(7)(8).…”