Shorter CAG repeat length in the androgen receptor gene is associated with more aggressive forms of breast cancer

Abstract

The androgen receptor (AR) is a transcription factor mediating the action of androgens. The AR gene is localized on chromosome X and it contains a series of CAG trinucleotide repeats. The length of the CAG repeats varies among individuals and this polymorphism is believed to be related to AR transcriptional activity. Studies have shown that fewer CAG repeats are associated with an increased risk as well as more aggressive forms of prostate cancer. Although AR is expressed in breast cancer and the impact of androgen and AR on breast cancer has been recognized, the role of the CAG repeats in breast cancer remains unknown. In this study, we measured the CAG repeats in breast cancer tissue using a PCR-based method. Of the 133 patients with primary breast cancer, 102 were heterozygous and 31 were homozygous. The mean CAG repeat number for homozygous women was 21; for heterozygous women the repeat number mean was 20 for the short allele and 24 for the long allele. The length of CAG repeats either in one allele or in both alleles was inversely correlated with the histological grade of breast cancer (r = -0.23 or -0.26, respectively, p < 0.05). An association between positive lymph nodes and fewer CAG repeats in both alleles was also suggested (p = 0.06). Furthermore, survival analysis indicated that the total number of CAG repeats in both alleles was associated with patient overall survival. With every CAG repeat increase, there was a 6% reduction in the risk of death (RR = 0.94, p = 0.03). The association remained significant after controlling for the homozygous and heterozygous status (RR = 0.92, p = 0.01). The association became no longer significant when clinical and pathological variables were adjusted in the analysis but this could be due to the reduction of sample size in the multivariate analysis. CAG heterozygosity and difference in number of CAG repeats between the two alleles were not associated with either disease features or patient survival. Our results suggest that longer CAG repeats may occur more frequently in less aggressive cancer and that the CAG repeats may play a role in breast cancer progression.

Androgen receptor CAG repeat length in Jewish Israeli women who are BRCA1/2 mutation carriers: association with breast/ovarian cancer phenotype

“…24 Given the endocrine dependency of breast cancer and the effect that androgenic pathway has on breast tissue proliferation, 22,25 it is plausible that an increased androgen transactivation may promote uncontrolled breast epithelial tissue proliferation. As a further support for the putative role that the short CAG repeat plays in determining breast cancer phenotype, Yu et al 26 suggested an association between shorter CAG repeat length and tumour grade and survival. Several studies reported of an association between the shorter AR (CAG)n repeat and the risk for prostate cancer.…”

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

“…By contrast, some studies have not confirmed this relationship (e.g. [56,57]), and Yu et al [58] found a negative correlation between CAG repeat length and tumor aggressiveness in breast cancer. There is also evidence that CAG repeats evolve through selection in the somatic evolution of colon cancer [59], which indicates that shorter repeat length, may be associated with other forms of cancer as well.…”

Alleles with short CAG and GGN repeats in the androgen receptor gene are associated with benign endometrial cancer

“…In breast cancer, shorter CAG tracts have been associated with a higher grade and with lymph node involvement. 5,36 In ovarian cancer no association was found between CAG fragment length and age at diagnosis, grade or stage. 12 Finally, the data related to prostate cancer is conflictive, although different reports have suggested that a shorter CAG repeat is predictive of a higher grade, lymph node-positive disease and an advanced stage.…”

“…The data published about the prognostic value of both repeats in other steroid-hormone related tumors differ from our findings in EC. Short CAG repeats have been found to be predictive of a worse clinical outcome in breast, 5 ovarian, 12 and prostate cancers. 9 Conversely, the short GGN alleles have been associated with a good prognosis in prostate cancer.…”

“…4 Several epidemiologic studies have related the CAG polymorphism with the risk of developing some gynecological and urological, steroid hormone-related tumors, such as breast, ovarian, and prostate cancers, although discrepant results have also been reported. [5][6][7][8] The CAG tract has been associated with some prognostic variables of the above-mentioned cancers and even with the clinical evolution of patients. [9][10][11][12] This suggests that variation in the AR activity promoted by fluctuations in the length of the CAG repeat may affect the progression of tumors as well as influence their development.…”