Expression of androgen receptor splice variants in clinical breast cancers
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(Published version)
Date
2015
Authors
Hickey, T.
Irvine, C.
Dvinge, H.
Tarulli, G.
Hanson, A.
Ryan, N.
Pickering, M.
Birrell, S.
Hu, D.
Mackenzie, P.
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Journal article
Citation
Oncotarget, 2015; 6(42):44728-44744
Statement of Responsibility
Theresa E. Hickey, Connie M. Irvine, Heidi Dvinge, Gerard A. Tarulli, Adrienne R. Hanson, Natalie K. Ryan, Marie A. Pickering, Stephen N. Birrell, Dong Gui Hu, Peter I. Mackenzie, Roslin Russell, Carlos Caldas, Ganesh V. Raj, Scott M. Dehm, Stephen R. Plymate, Robert K. Bradley, Wayne D. Tilley, Luke A. Selth
Conference Name
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 <i>AR</i> 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 <i>ex vivo</i> 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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Published: November 05, 2015
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