title: Expression of androgen receptor splice variants in clinical breast cancers.
abstract: The importance of androgen receptor (AR) signaling is increasingly being recognized in breast cancer, which has elicited clinical trials aimed at assessing the efficacy of androgen deprivation therapy (ADT) for metastatic disease. In prostate cancer, resistance to ADT is frequently associated with the emergence of androgen-independent splice variants of the AR (AR variants, AR-Vs) that lack the LBD and are constitutively active. Women with breast cancer may be prone to a similar phenomenon. Herein, we show that in addition to the prototypical transcript, the AR gene produces a diverse range of AR-V transcripts in primary breast tumors. The most frequently and highly expressed variant was AR-V7 (exons 1/2/3/CE3), which was detectable at the mRNA level in > 50% of all breast cancers and at the protein level in a subset of ERα-negative tumors. Functionally, AR-V7 is a constitutively active and ADT-resistant transcription factor that promotes growth and regulates a transcriptional program distinct from AR in ERα-negative breast cancer cells. Importantly, we provide ex vivo evidence that AR-V7 is upregulated by the AR antagonist enzalutamide in primary breast tumors. These findings have implications for treatment response in the ongoing clinical trials of ADT in breast cancer.
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Theresa E
authors.initials: TE
authors.lastname: Hickey
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Connie M
authors.initials: CM
authors.lastname: Irvine
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Seattle, WA 98109, USA.|Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Dvinge
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Tarulli
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Adrienne R
authors.initials: AR
authors.lastname: Hanson
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Ryan
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Pickering
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Birrell
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia.
authors.forename: Dong Gui
authors.initials: DG
authors.lastname: Hu
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Mackenzie
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55905, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
authors.affiliation: Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Seattle, WA 98109, USA.|Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Bradley
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.|Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia.|Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Selth
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001549:Benzamides; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D020033:Protein Isoforms; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009570:Nitriles; D020033:Protein Isoforms; D012333:RNA, Messenger; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: alternative splicing; androgen deprivation therapy; androgen receptor; biomarker; breast cancer