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.
Bibliographical noteFunding Information:
The authors thank Dr. Lisa Butler for useful discussions and Dr. Shalini Jindal for assessment of tissue histology. We are also grateful to the surgeons who provided clinical specimens, the staff at Burnside War Memorial Hospital Breast Clinic and Flinders Medical Centre, and the women who consented to this study. The results published here are in part based on data generated by The Cancer Genome Atlas, established by the National Cancer Institute and the National Human Genome Research Institute, and we are grateful to the specimen donors and relevant research groups associated with this project.
- Alternative splicing
- Androgen deprivation therapy
- Androgen receptor
- Breast cancer