Functional characterization of androgen receptor in two patient-derived xenograft models of triple negative breast cancer. Issue 206 (February 2021)

• Record Type: Journal Article
• Authors: Wang, Xiaoqiang; Petrossian, Karineh; Huang, Miao-Juei; Saeki, Kohei; Kanaya, Noriko; Chang, Gregory; Somlo, George; Chen, Shiuan
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 206(2021)
• Publication Date: 2021-02
• Subjects: AR androgen receptor -- ASCO/CAP American Society of Clinical Oncology / College of American Pathologists -- BL1 basal-like 1 -- BL2 basal-like 2 -- DHT dihydrotestosterone -- ER estrogen receptor -- FDR false discovery rate -- FISH fluorescence in situ hybridization -- GSEA Gene Set Enrichment Analysis -- HER2 human epidermal growth factor -- H&E hematoxylin and eosin -- IHC immunohistochemistry -- IPA Ingenuity Pathway Analysis -- LAR luminal androgen receptor -- PCA principal component analysis -- PDXs patient-derived xenografts -- PR progesterone receptor -- RNA-Seq RNA sequencing -- RPPA reverse phase protein array -- SWI/SNF SWItch/Sucrose Non-Fermentable -- TCGA The Cancer Genome Atlas -- TNBC triple negative breast cancer -- TSR tumor-stroma ratio -- WESeq whole exome sequencing; Androgen receptor -- Triple negative breast cancer -- Patient-derived xenograft -- RNA sequencing; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2020.105791
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Two AR-positive TNBC PDX models were derived and molecularly characterized. Two PDXs harbored low levels of functional AR, which was transcriptionally activated by AR agonist (DHT). Two PDXs exhibited highly different patterns of tumor growth and distinct transcriptional profiles upon DHT treatment. Two PDXs represented different molecular subtypes of TNBC. Our results do not support that AR is a suitable therapeutic target in TNBC. Abstract: 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.