Interactions Between FAM3B and Androgen Receptor in Driving Prostate Cancer Progression
Abstract
A critical challenge in the clinical management of prostate cancer is to identify lethal from non-lethal disease. Currently, only a small fraction of patients develops recurrence and metastasis and eventually dies from prostate cancer. For most men diagnosed with prostate cancer, the cancer is found at an early stage. These men often have several treatment options to consider. Comparing the efficacies and possible side effects of various treatment options to choose the optimal treatment is not easy. Thus, a reliable marker to predict the clinical behavior of prostate cancer early is needed to reach a correct decision for effective treatment of the disease while sparing patients from unnecessary side effects of overtreatment. The TMPRSS2-ERG fusions, the abnormal joining of the TMPRSS2 gene with the ERG gene, occur in about 50% of human prostate cancer cases and are an early event during cancer development. About half of the fusions are generated through deletion of the region between these two genes, and the other half is formed when cancer cells reshuffle their DNA materials. Compared to the latter, the deletion class of prostate cancer is associated with higher tumor stage, life-threatening metastasis, therapy resistance, and shorter patient survival. Despite the substantially greater aggressiveness of the deletion class of prostate cancer, our understanding of how the deletion leads to poor patient outcome is unacceptably poor. In our preliminary studies, through studying gene expression data from close to 400 prostate cancer samples with clinical outcomes, we discovered a gene in this deleted region, FAM3B, the loss of which is more strongly associated with poor clinical outcome than the loss of any other gene in this region. FAM3B levels are widely reduced in prostate cancers with aggressive behavior. Patients with low-FAM3B tumors are highly likely to end up with disease recurrence following complete surgical removal of their prostate. Laboratory studies showed that low FAM3B expression promotes the aggressive properties of prostate cancer cells. These results suggest that loss of FAM3B could drive prostate cancer progression to a lethal phenotype. Through cross-interrogating clinical data and preclinical data and subsequent experimental validation, we found the existence of a double-negative feedback loop between FAM3B and androgen receptor, the ultimate driver gene of most prostate cancer. In normal prostate gland, this loop acts as a rheostat to keep androgen receptor activity in check. Disruption of this loop as a result of FAM3B loss in prostate cancer unleashes androgen receptor activity, leading to further loss of FAM3B to push disease progression. Significantly, drugs that can restore FAM3B expression have been proven to be safe in clinical trials. Using these drugs to restore FAM3B level may serve as an effective strategy to stop FAM3B-low prostate cancer from progressing to a more aggressive stage. In this application, we have designed a series of studies in prostate cancer cells, a genetically modified mouse model, patient-derived tumor models, and clinical prostate cancer samples to validate this idea to help position low FAM3B level, alone or combined with overactive androgen receptor, as a biomarker of aggressive disease and to define the mechanisms by which FAM3B and androgen receptor reciprocally feedback regulate each other. Ultimate Applicability of the Research: Our proposed study can help prostate cancer patients in at least two ways. First, the immediate application lies in the use of a FAM3B test to guide treatment decision. In patients who have undergone surgery, the detection of FAM3B loss in the cancer suggests that additional treatments should be given immediately after surgery, as the cancer is highly likely to return. Cases without FAM3B loss can feel reassured that they do not need additional therapies, as the chances that the cancer returns are far lower. Furt
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010517
Entities
People
- Yan Dong
Organizations
- Tulane University of Louisiana
- United States Army