Extensive efforts, through cell line-based models, have been made to characterize the
androgen receptor (AR) signaling pathway in
triple-negative breast cancer (TNBC). However, these efforts have not yet reached a consensus with regards to the mechanism of AR in TNBC. Considering that patient-derived xenografts (PDXs) are more appropriate than cell line-based models for recapitulating the structural and molecular features of a patient's
tumor, we have identified and molecularly characterized two new AR-positive TNBC PDX models and assessed the impacts of AR agonist [
dihydrotestosterone (DHT)] and antagonist (
enzalutamide) on
tumor growth and gene expression profiles by utilizing immunohistochemistry, western blots, and
RNA-Seq analyses. Two PDX models, termed TN1 and TN2, were derived from two grade-3 TNBC
tumors, each harboring 1∼5% of AR nuclear positive
cancer cells. DHT activated AR in both PDX
tumors by increasing nuclear localization and AR
protein levels. However, the endpoint
tumor volume of DHT-treated TN1 was 3-folds smaller than that of non-treated TN1
tumors. Conversely, the endpoint
tumor volume of DHT-treated TN2 was 2-folds larger than that of non-treated TN2. Moreover,
enzalutamide failed to antagonize DHT-induced
tumor growth in TN2. The
RNA-Seq analyses revealed that DHT mainly suppressed gene expression in TN1 (961 down-regulated genes versus 149 up-regulated genes), while DHT promoted gene expression in TN2 (673 up-regulated genes versus 192 down-regulated genes).
RNA-Seq data predicted distinct TNBC molecular subtypes for TN1 and TN2. TN1 correlated to a basal-like 1 (BL1) subtype, and TN2 correlated to a basal-like 2 (BL2) subtype. These analyses suggest that TN1 and TN2, which both express functional AR, are two molecularly distinct PDX models. The molecular characterization of these PDX models expands our current knowledge on AR-positive TNBC. Our results do not support that AR is a suitable therapeutic target in TNBC. To our best knowledge, the molecular mechanisms of AR in TNBC are equivocal and should be evaluated using clinically relevant models, considering both the heterogeneous expression of AR in TNBC and the general complexities of AR signaling.