AR Pathway Activity Correlates with AR Expression in a HER2-dependent Manner and Serves As a Better Prognostic Factor in Breast Cancer

Background: Androgen receptor (AR) antagonists are currently tested in multiple clinical trials for different breast cancer (BC) subtypes, which emphasizes the need for clarifying the role of AR in this type of cancer. Previous studies showed that AR expression was associated with a favorable prognosis in ER-positive BC. However, the true biological effect of AR signaling in BC is not clear.

Methods: An AR pathway signature was generated to compute AR pathway activity in BCs (n = 6439) from 46 microarray datasets. Associations of AR pathway activity and AR expression with BC prognosis were compared by survival analysis.

Results: AR pathway activity showed moderate positive and negative correlations with AR expression in HER2-positive and HER2-negative BCs, respectively. AR pathway activity increased while AR expression decreased in ER-negative BCs. Like ER and progesterone receptor (PR) expression, AR expression was also negatively associated with tumor grade, neoadjuvant response, and recurrence risk in BC. By contrast, AR pathway activity was positively, and more significantly, associated with these clinical features. Moreover, the AR pathway, but not AR expression, was significantly associated with recurrence risk in BC patients treated with endocrine therapy. These data suggest that, although AR expression probably reflects well-differentiated states of BC and is thus associated with favorable prognosis in BC, the biological effects of AR signaling confers worse outcomes in BC.

Conclusions: Our findings encourage the continued evaluation of AR antagonists for BC treatment and support that AR pathway activity serves as a better prognostic factor than AR expression in BC.