Resolving the Roles of FOXO Transcription Factors as Effectors of Pten in Prostate Cancer

PUBLIC ABSTRACT

Prostate cancer kills approximately 30,000 men in the United States each year. Advanced prostate cancer is the most difficult to treat, because it is oftentimes resistant to conventional chemotherapy regiments. Tumor suppressor genes are genes that naturally inhibit cancer progression. Our lab studies a tumor suppressor PTEN that is lost in 60% of advanced prostate tumors. This loss is strongly associated with a poor prognosis as well as refractory response to chemotherapy. It is our goal to investigate the PTEN pathway in order to ultimately better treat advanced prostate cancer.

The goal of our work is to identify targets of PTEN that are vital for tumor suppression in order to ultimately discover ways to activate these targets to prevent tumor progression. Our first step is to ascertain which targets of PTEN are essential in preventing prostate tumor progression. After this, we can investigate how these targets are regulated and devise strategies to activate them in the absence of PTEN therapeutically. Three transcription factors (FOXO1a, FOXO3a, and FOXO4) are universally argued to be critical effectors of PTEN in prostate tumor suppression. Many studies in which these transcription factors are overexpressed suggest that these factors are interchangeable. However, mouse model studies as well as work in our lab suggest that these factors act very distinctively. To resolve these discrepancies, we propose to directly investigate the role of each of these transcription factors in prostate cancer.

First, we will investigate the roles of FOXO transcription factors in PTEN-mediated gene induction. Specifically, we will diminish the expression of each FOXO transcription factor and determine whether this affects the PTEN-mediated induction of genes involved in prostate cancer. Also, we will determine whether the FOXO transcription factors directly bind the promoters of genes that are involved in prostate cancer. In this manner, we will delineate the mechanisms utilized by PTEN to activate target genes involved in inhibiting prostate cancer. In addition to this approach, we will directly assess whether any of the FOXO transcription factors is lost in prostate cancer, suggesting a role for such a factor in preventing prostate cancer. To do this, we will stain prostate tumors for expression of FOXO1a, FOXO3a, and FOXO4 as well as sequence these genes in DNA obtained from prostate tumors. In this way, we will know whether any of the FOXO transcription factors is downregulated in prostate cancer. These experiments will help us gauge the importance of each of these transcription factors in inhibiting prostate cancer. For example, if FOXO4 were mutated in a high fraction of prostate tumors whereas FOXO1a and FOXO3a were not, then one would conclude that the loss of FOXO4 is more important for prostate cancer progression.

All of the experiments detailed in this grant should shed light on the contributions of FOXO transcription factors in inhibiting prostate cancer. The identification and characterization of important PTEN targets (such as particular FOXO transcription factors) makes it much more feasible to devise a scheme in which one can bypass the requirement of PTEN in order to ultimately better treat prostate cancer.