@article{eca58476d3094fc59cd6c307e6038309,
title = "Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer",
abstract = "Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.",
keywords = "ATAD2, BRD2, BRD4, BROMO-10, androgen receptor, bromodomain inhibitor, castration-resistant prostate cancer, chromatin",
author = "Alfonso Urbanucci and Barfeld, {Stefan J.} and Ville Kyt{\"o}l{\"a} and Itkonen, {Harri M.} and Coleman, {Ilsa M.} and Daniel Vod{\'a}k and Liisa Sj{\"o}blom and Xia Sheng and Teemu Tolonen and Sarah Minner and Christoph Burdelski and Kivinummi, {Kati K.} and Annika Kohvakka and Steven Kregel and Mandeep Takhar and Mohammed Alshalalfa and Elai Davicioni and Nicholas Erho and Paul Lloyd and Karnes, {R. Jeffrey} and Ross, {Ashley E.} and Schaeffer, {Edward M.} and {Vander Griend}, {Donald J.} and Stefan Knapp and Eva Corey and Feng, {Felix Y.} and Nelson, {Peter S.} and Fahri Saatcioglu and Knudsen, {Karen E.} and Tammela, {Teuvo L.J.} and Guido Sauter and Thorsten Schlomm and Matti Nykter and Tapio Visakorpi and Mills, {Ian G.}",
note = "Funding Information: We thank Ms. P{\"a}ivi Martikainen for the skillful technical assistance. We acknowledge the last scientific contribution of our beloved Ms. Mariitta Vakkuri to this work. A.U. is supported by the South-East Norway Health Authorities (Helse Sor-Ost grant ID 2014040) at the Oslo University Hospital and the Norwegian Centre for Molecular Medicine. I.M. has been funded by the MLS (390000 and 143295), Helse Sor-Ost (2014040), Norwegian Research Council (230559), and the Faculty of Medicine at the Oslo University Hospital. P.S.N., E.C., and I.M.C. are supported by NIH grants P50CA097186 and P01CA163227, and the Prostate Cancer Foundation. H.M.I. is supported by the Norwegian Cancer Society (711072, 102032, and 4521627). S. Knapp is grateful for support by the SGC, a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, S{\~a}o Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust. The funders had no role in the study design, data collection and analysis, the decision to publish, or preparation of the article. Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = jun,
day = "6",
doi = "10.1016/j.celrep.2017.05.049",
language = "English (US)",
volume = "19",
pages = "2045--2059",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}
