Constitutively active androgen receptor supports the metastatic phenotype of endocrine-resistant hormone receptor-positi
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(2020) 18:154
RESEARCH
Open Access
Constitutively active androgen receptor supports the metastatic phenotype of endocrine-resistant hormone receptorpositive breast cancer Shaymaa Bahnassy1, Hariprasad Thangavel2, Maram Quttina1, Ashfia Fatima Khan1, Dhanya Dhanyalayam1, Joan Ritho3, Samaneh Karami1, Jing Ren4 and Tasneem Bawa-Khalfe1*
Abstract Background: Hormone 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. Methods: AR 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. Results: Sustained 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 chromatinbound, and transcriptionally active. Constitutive SUMO-AR initiates a gene-expression profile that favors epithelialmesenchymal transition. Enz combined with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa. Conclusion: Targeting both unmodified and SUMO-modified AR prevents the metastatic progression of HR+ BCa with ET-R. Keywords: HR+ breast cancer, Endocrine resistance, Androgen receptor, SUMO, Enzalutamide
* Correspondence: [email protected] 1 Center for Nuclear Receptors & Cell Signaling, Department of Biology & Biochemistry, University of Houston, 3517 Cullen Blvd, SERC Bldg, Rm 3010, Houston, TX 77204-5056, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article'
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