Expression of androgen receptor splice variants in clinical breast cancers

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

Research output: Contribution to journalArticle

48 Scopus citations

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 ERa-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 ERa-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.

Original languageEnglish (US)
Pages (from-to)44728-44744
Number of pages17
JournalOncotarget
Volume6
Issue number42
DOIs
StatePublished - Jan 1 2015

Keywords

  • Alternative splicing
  • Androgen deprivation therapy
  • Androgen receptor
  • Biomarker
  • Breast cancer

ASJC Scopus subject areas

  • Oncology

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    Hickey, T. E., Irvine, C. M., Dvinge, H., Tarulli, G. A., Hanson, A. R., Ryan, N. K., Pickering, M. A., Birrell, S. N., Hu, D. G., Mackenzie, P. I., Russell, R., Caldas, C., Raj, G. V., Dehm, S. M., Plymate, S. R., Bradley, R. K., Tilley, W. D., & Selth, L. A. (2015). Expression of androgen receptor splice variants in clinical breast cancers. Oncotarget, 6(42), 44728-44744. https://doi.org/10.18632/oncotarget.6296