Constitutively active androgen receptor supports the metastatic phenotype of endocrine-resistant hormone receptor-positive breast cancer

Cell Communication and Signaling

Shaymaa Bahnassy¹  Dhanya Dhanyalayam¹  Maram Quttina¹  Tasneem Bawa-Khalfe¹  Ashfia Fatima Khan¹  Samaneh Karami¹  Jing Ren²  Joan Ritho³  Hariprasad Thangavel⁴ 

[1] Center for Nuclear Receptors & Cell Signaling, Department of Biology & Biochemistry, University of Houston, 3517 Cullen Blvd, SERC Bldg, Rm 3010, 77204-5056, Houston, TX, USA;Center for Precision Medicine, Department of Medicine, University of Missouri, 65212, Columbia, MO, USA;Department of Biology, Stanford University, 94305, Stanford, CA, USA;Department of Pharmacy Practice and Translational Research, College of Pharmacy, University of Houston, 77204, Houston, TX, USA;

关键词: HR+ breast cancer;    Endocrine resistance;    Androgen receptor;    SUMO;    Enzalutamide;   

DOI  :  10.1186/s12964-020-00649-z

来源: Springer

【 摘 要 】

BackgroundHormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed subtype. Acquired and intrinsic resistance to conventional endocrine therapy (ET) commonly occurs and prompts incurable metastatic disease. Hence, ET-resistant (ET-R) HR+ BCa presents a therapeutic challenge. Previous studies show elevated androgen receptor (AR) that supports resistance to ET tamoxifen and correlates with HR+ BCa metastasis. Yet surprisingly, studies with AR-blocker enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. We now report that a constitutively active, unique from canonical Enz-targeted, AR accumulates in endocrine resistant HR+ BCa cells.MethodsAR protein profiles in acquired and intrinsic ET-R HR + -BCa were defined with cell-free modification tests, in-house in-vivo SUMOylation assays, and PLA imaging. Genomic activity of native AR and modified-AR mimetic was tested with reporter assays and limited transcriptome analysis. Spheroid growth and migration studies were used to evaluate inhibitory actions of Enz and combinatorial therapy.ResultsSustained higher molecular weight SUMO-modified AR (SUMO-AR) persists in acquired and intrinsic ET-R BCa cell lines. Concurrently, SUMO isoforms and global SUMO-modified proteome also accumulates in the same cell lines. We identified AR as a novel substrate for the SUMO-E3 ligase HSPB1/Hsp27. Independent of ligand, SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation, enriched in the nucleus, readily chromatin-bound, and transcriptionally active. Constitutive SUMO-AR initiates a gene-expression profile that favors epithelial-mesenchymal transition. Enz combined with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa.ConclusionTargeting both unmodified and SUMO-modified AR prevents the metastatic progression of HR+ BCa with ET-R.1cz6dozgZCQes7_eQqKRNVVideo abstract

【 授权许可】

CC BY