Purpose: The androgen receptor (AR) harbors a polymorphic CAG repeat sequence in exon 1, coding for a polyglutamine tract whose length inversely correlates with AR transactivation function. AIB1, an steroid receptor co-activator, expresses a similar polymorphic glutamine sequence within the carboxy-terminal coding region. We hypothesize that genotypic variations in the androgen signaling pathway promote aggressive epithelial ovarian cancer biology, and sought to examine AR-AIB1 interactions in malignant ovarian epithelial cells and to determine the impact of AR and AIB1 genotype on clinical outcome. Experimental Design. AR-null SKOV-3 cells were stably transfected with AR and subjected to confocal laser scanning microscopy (CLSM) after treatment with dihydrotestosterone (DHT). Cells were labeled with monoclonal anti-AR and anti-AIB1 antibodies. Genotype analysis of the AR and AIB1 CAG repeat regions was performed on 89 patients with epithelial ovarian cancer. Medical records were reviewed for clinico-pathologic factors and survival. Data were examined using the Chi-squared test and Kaplan-Meier survival and Cox Regression analyses. Results: Nuclear translocation of AIB1 was identified on CLSM with expression of AR. Co-localization studies also suggested direct interaction between AR and AIB1. Patients with short AR and AIB1 genotype (< 19 and < 28 CAG repeats, respectively) demonstrated statistically shorter time to disease recurrence compared to those with long AR and AIB1 genotype (10 versus 23 months, p = 0.001). Patients with short AR and AIB1 genotypes also demonstrated decreased overall survival (median, 34 months) compared to those with long genotypes (median survival > 62 months, p = 0.01). After controlling for age, stage, grade, and suboptimal cytoreduction, multivariate analysis identified the presence of short AR-AIB1 genotype as an independent poor prognostic factor for overall survival (p = 0.05). Conclusions: These data suggest AR and AIB1 directly interact in malignant epithelial ovarian cells, and that this combination of short genotypes in key proteins of the androgen signaling pathway may promote an aggressive phenotype of epithelial ovarian cancer.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]