Journal
ONCOTARGET
Volume 6, Issue 42, Pages 44728-44744Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6296
Keywords
androgen receptor; breast cancer; androgen deprivation therapy; alternative splicing; biomarker
Categories
Funding
- Susan G. Komen for the Cure [BCTR0601118]
- National Breast Cancer Foundation of Australia [NC-12-21]
- Prostate Cancer Foundation of Australia/Cancer Australia [1043482]
- Ray and Shirl Norman Cancer Research Trust
- U.S. Department of Defense Prostate Cancer Research Program [W81XWH-13-2-0093]
- National Health and Medical Research Council of Australia [1008349]
- National Institutes of Health/National Cancer Institute [P50 CA138293]
- Prostate Cancer Foundation
- US Department of Defense Breast Cancer Research Program [W81XWH-11-1-0592, W81XWH-14-1-0044]
- Cancer Research UK [16942] Funding Source: researchfish
- National Breast Cancer Foundation [PD-13-03] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10154] Funding Source: researchfish
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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 ER alpha-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 ER alpha-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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