Expression of androgen receptor splice variants in clinical breast cancers
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Theresa E. Hickey1,*, Connie M. Irvine1,*, Heidi Dvinge2,3, Gerard A. Tarulli1, Adrienne R. Hanson1, Natalie K. Ryan1, Marie A. Pickering1, Stephen N. Birrell1, Dong Gui Hu4, Peter I. Mackenzie4, Roslin Russell5, Carlos Caldas5, Ganesh V. Raj6, Scott M. Dehm7,8, Stephen R. Plymate9, Robert K. Bradley2,3, Wayne D. Tilley1,10, Luke A. Selth1,10
1Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, The University of Adelaide, SA 5005, Australia
2Computational Biology Program, Public Health Sciences Division, Seattle, WA 98109, USA
3Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
4Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia
5Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
6Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
7Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA
8Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55905, USA
9Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA
10Freemasons Foundation Centre for Men’s Health, School of Medicine, The University of Adelaide, SA 5005, Australia
*These authors have contributed equally to this work
Luke A. Selth, e-mail: [email protected]
Wayne D. Tilley, e-mail: [email protected]
Keywords: androgen receptor, breast cancer, androgen deprivation therapy, alternative splicing, biomarker
Received: October 19, 2015 Accepted: October 26, 2015 Published: November 05, 2015
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.
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