Expression of androgen receptor splice variants in clinical breast cancers
| Autor: | Gerard A. Tarulli, Carlos Caldas, Theresa E. Hickey, Wayne D. Tilley, Dong Gui Hu, Stephen R. Plymate, Ganesh V. Raj, Luke A. Selth, Natalie K. Ryan, Adrienne R. Hanson, Stephen N. Birrell, Peter I. Mackenzie, Scott M. Dehm, Connie M. Irvine, Heidi Dvinge, Marie A. Pickering, Roslin Russell, Robert K. Bradley |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Oncology
Gerontology medicine.medical_specialty Time Factors Antineoplastic Agents Hormonal Transcription Genetic Breast Neoplasms androgen deprivation therapy Transfection Androgen deprivation therapy Prostate cancer chemistry.chemical_compound alternative splicing Breast cancer breast cancer Internal medicine androgen receptor Databases Genetic Nitriles Phenylthiohydantoin medicine Enzalutamide Humans Protein Isoforms RNA Messenger business.industry Public health Gene Expression Profiling Estrogen Receptor alpha Cancer Androgen Antagonists medicine.disease 3. Good health Androgen receptor Clinical trial Gene Expression Regulation Neoplastic HEK293 Cells chemistry Drug Resistance Neoplasm Receptors Androgen Benzamides MCF-7 Cells biomarker Female RNA Interference business Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Theresa E. Hickey 1, * , Connie M. Irvine 1, * , Heidi Dvinge 2, 3 , Gerard A. Tarulli 1 , Adrienne R. Hanson 1 , Natalie K. Ryan 1 , Marie A. Pickering 1 , Stephen N. Birrell 1 , Dong Gui Hu 4 , Peter I. Mackenzie 4 , Roslin Russell 5 , Carlos Caldas 5 , Ganesh V. Raj 6 , Scott M. Dehm 7, 8 , Stephen R. Plymate 9 , Robert K. Bradley 2, 3 , Wayne D. Tilley 1, 10 , Luke A. Selth 1, 10 1 Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia 2 Computational Biology Program, Public Health Sciences Division, Seattle, WA 98109, USA 3 Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA 4 Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia 5 Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK 6 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 7 Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA 8 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55905, USA 9 Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA 10 Freemasons Foundation Centre for Men’s Health, School of Medicine, The University of Adelaide, SA 5005, Australia * These authors have contributed equally to this work Correspondence to: Luke A. Selth, e-mail: luke.selth@adelaide.edu.au Wayne D. Tilley, e-mail: wayne.tilley@adelaide.edu.au Keywords: androgen receptor, breast cancer, androgen deprivation therapy, alternative splicing, biomarker Received: October 19, 2015 Accepted: October 26, 2015 Published: November 05, 2015 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. |
| Databáze: | OpenAIRE |
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