Short polyglutamine tracts in the androgen receptor are protective againstbreast cancer in the general population

We studied the association of breast cancer with the polymorphic polyglutam ine repeat of the androgen receptor (AR) in 255 incident cases of breast ca ncer and 461 matched controls from the Quebec City metropolitan area. Women for whom the sum of both of the AR (CAG)n-repeats alleles is 39 or less (s hort-allele AR genotypes) have one-half the risk of breast cancer compared with women for whom the sum of AR (CAG)n-repeats is 40 or more [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3-0.83; P = 0.007]. This associa tion is stronger in postmenopausal women (180 cases, 297 controls; OR, 0.36 ; 95% CI, 0.19-0.7; P = 0.003). We also observed an interaction between the type of menopause (natural versus surgical) and the AR genotype on breast cancer risk. Alternately, when subjects were grouped according to their (CA G)n-repeat genotype [homozygous for short alleles (CAG)n less than or equal to 20; other genotypes ("long allele")], results were similar (OR. 0.5; 95 % Cl, 0.27-0.82; P = 0.007). Thus, women with short-alleles AR genotypes ap pear to be protected against breast cancer. Short-alleles AR genotypes were observed in 16% of the general population as represented by the control gr oup. Short polyglutamine repeats in the AR protein have been reported to be associated with an increase in the capacity of the receptor to activate tr anscription of reporter genes in vitro. Furthermore, androgens have been pr eviously shown to inhibit in vitro the growth of breast cancer cell lines. This suggests that differences in the number of polyglutamines in the AR pr otein may influence individual risk of breast cancer, especially in postmen opausal women, and that this apparent protection could be the consequence o f an increased response/sensitivity to androgens.