Androgen receptor polymorphisms and endometrial cancer risk

Abstract

The androgen receptor (AR) gene is a transcription factor responsible for mediating the physiological effects of androgens. Evidence suggests that androgens and the androgen receptor are involved in uterine cell proliferation. A polymorphic CAG repeat in exon 1 of the AR gene encodes a polyglutamine tract that is inversely correlated with the transcriptional activity of this gene. We assessed the association between the functional CAG repeat polymorphism and AR haplotypes and the risk of endometrial cancer in two nested case-control studies within the Nurses' Health Study (n 5 222 cases, 666 controls) and the Women's Health Study (n 5 137 cases, 411 controls) using conditional and unconditional logistic regression. Associations between AR CAG repeat polymorphism and endometrial cancer risk were similar in the 2 case-control studies. In the pooled analysis, women with an average repeat allele 22 repeats compared to <22 repeats were at a statistically significant decreased risk of endometrial cancer (odds ratio (OR) 5 0.76; 95% confidence interval (CI), 0.59-0.98). Women with one or two long alleles (27 repeats) compared to both alleles <22 repeats were also at a statistically significant decreased risk (OR 5 0.60; 95% CI, 0.36-0.99). We observed a modest yet statistically significant association for each one unit increase in the average repeat length and endometrial cancer risk (OR 5 0.94; 95% CI, 0.88-1.00). Associations for the AR CAG average repeat length and endometrial cancer risk differed by menopausal status (p 5 0.02). No significant associations between the AR haplotypes and endometrial cancer risk were observed. Our findings suggest that an increasing number of functional CAG repeats may be associated with endometrial carcinogenesis because of AR's reduced ability to recruit coregulators and other transcriptional components. (supplementary material for this article can be found on the International Journal of Cancer website at

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

“…This is supported by clinical studies, showing that increased tissue androgen sensitivity due to the presence of polymorphic shorter CAG repeat lengths in exon 1 of the AR was associated with increased uterine cancer risk (McGrath et al 2006). Similarly, in our recent study using global phosphatase and tensin homolog (PTEN) deletioninduced experimental uterine cancer, the severity of cancer progression was reduced when combined with global AR inactivation.…”

“…We provide evidence that this may be due to a downregulation of uterine PR expression, which normally protects against uterine cancer development. A clinical study suggested that increased androgen sensitivity (McGrath et al 2006) and increased androgen levels (Nagamani et al 1986, Smyczek-Gargya & Geppert 1992 in women were associated with a higher risk of uterine cancer, suggesting that androgen action may enhance or promote uterine cancer development. These clinical observations were supported by our recent study in which androgens acting via AR promoted PTEN deletion (global)-induced experimental uterine cancer (Choi et al 2015a).…”

Inflammatory events in endometrial adenocarcinoma

“…Overexpression of AR and steroid co-activators in the endometrium of women with polycystic ovarian syndrome has been described (Giudice 2006). It has been suggested that CAG repeat polymorphisms in the first exon of the AR gene could be associated with increased endometrial cancer risk due to reduced capacity of AR to recruit coregulators and transcriptional components (McGrath et al 2006), although this has been disputed (Ju & Kim 2007, Yang et al 2009). Expression of AR and 5a-reductase type 1 and type 2 enzymes has been detected in 88 and 80% of endometrial adenocarcinomas respectively (Ito et al 2002).…”

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

“…A polymorphic CAG repeat in exon 1 of the AR gene is well known to encode a polyglutamine tract and to increase the length of CAG repeat, which is also well known to be associated with decreased transactivation activities (Chamberlain et al 1994). Of particular interest, a statistically significant inverse association has been reported between increased CAG repeat length and endometrial carcinoma risk in case-control studies (McGrath et al 2006, Ashton et al 2010, although controversies exist (Yang et al 2009). On the other hand, Yang and coworkers evaluated 36 sex hormone-related genes using a tagging approach in a population-based case-control study of 417 endometrial carcinoma cases and reported that the possible evidence of the correlation with endometrial cancer risk could be the common genetic variation in 23:7 AR (Yang et al 2010).…”