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Short Polyglutamine Tracts in the Androgen Receptor Are Protective against Breast Cancer in the General Population¹

Unité de Recherche en Génétique Humaine et Moléculaire, Hôpital St-François-d’Assise-CHUQ and Département de Biologie médicale, Université Laval, Québec, Québec, G1L 3L5 [Y. G., V-I. F., S. D. F. R.]; Unité de recherche en santé publique, CHUL-CHUQ, and Département de médecine sociale et préventive, Université Laval, Beauport, Québec, G1E 7G9 [E. D., P. A., A. D.]; Centre de recherche [J. B.], and Centre des maladies du sein Deschênes-Fabia [J. R.], CHA de Québec, Hôpital du Saint-Sacrement, Québec, Québec, G1S 4L8; and Signalgene Inc, Montréal, Québec, H2M 2N9 [N. L.], Canada

We studied the association of breast cancer with the polymorphic polyglutamine repeat of the androgen receptor (AR) in 255 incident cases of breast cancer 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 (short-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 association 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 (CAG)n-repeat genotype [homozygous for short alleles (CAG)n 20; other genotypes ("long allele")], results were similar (OR. 0.5; 95% CI, 0.27–0.82; P = 0.007). Thus, women with short-alleles AR genotypes appear to be protected against breast cancer. Short-alleles AR genotypes were observed in 16% of the general population as represented by the control group. Short polyglutamine repeats in the AR protein have been reported to be associated with an increase in the capacity of the receptor to activate transcription of reporter genes in vitro. Furthermore, androgens have been previously shown to inhibit in vitro the growth of breast cancer cell lines. This suggests that differences in the number of polyglutamines in the AR protein may influence individual risk of breast cancer, especially in postmenopausal women, and that this apparent protection could be the consequence of an increased response/sensitivity to androgens.

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