GRB10 Sustains AR Activity by Interacting with PP2A in Prostate Cancer Cells
This week we profile a recent publication in the International Journal of Cancer from the
laboratory of Dr. Yuzhuo Wang (pictured) at BC Cancer and the Vancouver Prostate Centre.
Can you provide a brief overview of your lab’s current research focus?
Prostate cancer (PCa) remains one of the most common causes of cancer-related mortality in North American men. Androgen deprivation therapy is often the first-line therapy for high-risk and advanced PCa patients that initially leads to tumour regression with subsequent growth arrest and dormancy of prostate cancer. After this period of dormancy, however, most of these cases will progress to incurable castration-resistant prostate cancer (CRPC). One of our major research foci is to study tumour dormancy which is responsible for recurrence and metastasis that kills.
What is the significance of the findings in this publication?
Our knowledge on PCa dormancy is extremely limited due to the difficulty in acquiring clinical dormant PCa tissues and the lack of clinically relevant models. In the past decade, our lab has established a panel of hormone-naïve prostate cancer patient-derived xenograft (PDX) tumour lines that can mirror the disease courses and treatment responses of the patient tumours. Specifically, the response of hormone-naïve prostate cancer PDXs to androgen deprivation reflects the clinical findings with an initial remission, subsequent period of dormancy, and eventual CRPC development. Using these unique models, the group has previously discovered that a protein, called GRB10, is elevated during the dormancy and CRPC. In this study, we, for the first time, report GRB10 sustains androgen receptor (AR) activity in CRPC. Data from high-throughput proteomics analysis indicate that PP2A is a mediator of GRB10’s AR modulation. GRB10 interacts with PP2A and promotes its degradation, thereby protecting phosphorylated AR from dephosphorylation. This ultimately contributes to sustained active AR signaling which is critical for CRPC progression.
What are the next steps for this research?
We will further elucidate the pro-survival role of GRB10 and other crucial players in dormant cancer. Successful studies in this field will considerably improve our understanding of the mechanisms underlying cancer dormancy. Eventually we hope our research will establish a foundation for developing novel strategies for management and/or treatment of dormant cancer to prevent cancer relapse and metastasis.
This research was funded by:
This study was supported by Canadian Institutes of Health Research, Terry Fox Research Institute, Canadian Foundation for Translational Immunology, Urology Foundation, Mitacs Accelerate, and NIH Prostate Cancer SPORE.