Prostate Cancer Research
New Cancer Biomodule Regulating Prostate Cancer Initiation and Progression Identified
The prostate cancer research field is fast paced. PCF’s Science Department routinely holds scientific discussions with leading cancer researchers to stay abreast of the most recent prostate cancer publications. These meetings keep PCF at the cutting edge of prostate cancer research. This section provides summaries of these “Journal Club” meetings.
Proteins in the Hox regulatory network identified as potential tumor suppressors in prostate cancer initiation and progression.
July 16, 2012—Despite the fact that both the prostate and the seminal vesicles are functionally similar (sex accessory glands) and androgen-dependent, the incidence of cancers in these glands is vastly different: there are more than 250,000 cases of prostate cancer annually in the United States compared to less than fifty documented cases of seminal vesicle cancer. This profound difference in the development of malignant tumors in these neighboring sex accessory glands hints at unique differences between the prostate and seminal vesicle tissues which strongly predispose the prostate to cancer.
These differences were exploited by Dr. Donald Vander Griend and his research team at the University of Chicago who identified a novel cancer biomodule (i.e. a network of interacting proteins) unique to prostate epithelial cells. Genes in this network normally play critical roles in embryonic development and when dysregulated, lead to prostate cancer initiation and progression.
Dr. Vander Griend and his team studied the differences in gene expression profiles of normal prostate and seminal vesicle epithelial cells. Of the 447 differentially expressed genes, the team investigated genes dysregulated in cancer to narrow down on a set of genes that play important roles in embryonic development (HoxA9 and HoxB7) and their cofactors/regulators (Meis1, Meis 2 and Pbx1). The researchers compared the levels of expression of these genes in normal cells, primary prostate cancer tumor specimens and castration-resistant prostate cancer (CRPC) tumor specimens. They observed that levels of Meis 1, Meis 2 and Pbx1 decline as the cancer progresses and spreads. These differences in expression profiles of these three genes also correlated with the Gleason grade of prostate tumors (r = 0.98. p =0.02), with more aggressive, higher Gleason grade tumors expressing lower levels of Meis1, Meis2 and Pbx1 compared to lower Gleason grade cancers. Decreased expression levels of Meis1 and Meis2 also predicted worse overall patient survival, while elevated levels were associated with improved survival.
Differences in gene expression profiles of Meis 1, Meis 2 and Pbx1 could also 1) detect overall survival differences in a watchful-waiting patient cohort (n = 172, p = 0.05), 2) identify men who are more likely to recur post-prostatectomy (n = 78, p= 0.02), and 3) distinguish between normal prostate, primary tumor, and metastatic disease. This newly identified cancer biomodule is therefore prognostic for both prostate cancer recurrence and patient survival.
What exactly are the Meis 1 and 2 genes? These genes play crucial roles in early embryonic development. They assist a family of proteins called the Hox proteins in binding to specific genes and regulating their expression. These gene products are therefore important cofactors that impact normal embryonic development.
Recently, mutations in a Hox gene, HoxB13 were shown to be associated with an increased risk of developing prostate cancer. Interestingly, this mutation occurs in specific domain of HoxB13 that interacts with Meis. Therefore, interference of the Meis-Hox protein interactions, either by mutations (Hox B13 mutation) or through decreased expression (Meis 1 and Meis 2) is potentially a critical molecular event in prostate cancer development.
Meis genes have also been shown to play oncogenic roles in other cancers such as certain leukemias. This study by the team at University of Chicago provides the first evidence of the role of these genes in the initiation and progression of prostate cancer. Once validated, these genes (Meis 1, Meis 2 and Pbx1) and their products may serve as biomarkers for patient stratification as well as therapeutic targets.