Open AccessAR Is Not an Independent Marker for TNBC: The Lesson We Learn From Two PDX Models
Author(s) -
Xiaoqiang Wang,
Karineh Petrossian,
Miao-Juei Huang,
Kohei Saeki,
Noriko Kanaya,
Gregory Chang,
George Somlo,
Shiuan Chen
Publication year - 2021
Publication title -
journal of the endocrine society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.046
H-Index - 20
ISSN - 2472-1972
DOI - 10.1210/jendso/bvab048.1636
Subject(s) - androgen receptor , enzalutamide , triple negative breast cancer , cancer research , immunohistochemistry , subtyping , gene expression , gene , biology , cancer , chemistry , breast cancer , prostate cancer , genetics , computer science , immunology , programming language
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. On the other hand, patient-derived xenografts (PDXs) are generally considered more appropriate than cell line-based models for recapitulating the structural and molecular features of a patient’s tumor, but only a few have been reported to be AR-positive TNBC. In our study, we identified and molecularly characterized two new, AR-positive TNBC PDX models and assessed the impacts of AR agonist (DHT) and antagonist (enzalutamide) on tumor growth and gene expression profiles by utilizing immunohistochemistry (IHC), western blots, and RNA-Seq and TNBC subtyping analyses. Two PDX models, termed TN1 and TN2, were derived from two grade 3 TNBC tumors, each containing 1~5% of AR positive tumor cells. DHT activated AR in both PDX tumors by increasing AR nuclear localization and 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 suppressed gene expression in TN1 (961 down-regulated genes versus 149 up-regulated genes), while the DHT promoted gene expression in TN2 (673 up-regulated genes versus192 down-regulated genes). TNBC subtyping analyses based on RNA-Seq data predicted distinct molecular subtypes of 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 that expand our current knowledge of 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.