CREB Activation: A Gene Signature and Control Switch in Prostate Cancer
Abstract
Background: Cell fate decisions, i.e., whether a particular cell will remain as a primitive cell or whether it will commit to become part of a specific tissue (i.e., differentiate) is a highly controlled and complex process. It is typically driven by sequential waves of new gene expression, controlled by a set of specialized transcription factors that control both the timing and extent of gene expression. Many researchers believe that cancer arises in part from a reversion to this more primitive cell state such that the cells can no longer properly decide their true cell fate. On the other hand, cancer is also known to arise from a distinct set of gene mutations (oncogenes) that alter how these genes function and lead to aberrant cell proliferation. Thus, cancer can be described as over-proliferation of a misguided cell that can t differentiate properly. However, what is not clear is how these two processes, oncogenes and failure of cell differentiation, are linked. The reason for this is that each tissue has a unique set of primitive cells, transcription factors, and oncogenes. Therefore, to understand how cancer arises, and thus to accurately diagnose and treat it, it is necessary to understand all these details and their interactions for each tissue. Unfortunately for prostate cancer (PCa) patients, very little is known about these interactions in the human prostate. Hypothesis: Many men develop PCa, and for most it will not be life-threatening. However, for some it will be, and unfortunately, we cannot predict which patients this will be, making treatment decisions difficult. Our premise for this study is that interactions between oncogenes and a specific set of transcription factors that control prostate cell fate/differentiation dictate the severity of prostate cancer. In particular, we are focusing on the Pten oncogene, whose loss promotes PCa. Furthermore, of the known PCa oncogenes, Pten loss is most closely aligned with poor outcomes in patients. Thus, by understanding how Pten controls cell fate through a specific set of transcription factors, we believe it will be possible to identify additional markers to more precisely predict which patients will develop life-threatening disease. Aims: Towards this end, we identified two related transcription factors, CREB1 and ATF1, whose activity is greatly enhanced in tumor cells lacking Pten. We demonstrate that CREB1 and ATF1 are required for normal human prostate cell differentiation, but in the tumor cells lacking Pten, it regulates a completely different set of genes and prevents the cells from committing to their proper cell fate. Using our unique human prostate differentiation model, we will (1) determine the role of CREB1/ATF1 in differentiation and oncogenesis, (2) identify the CREB1/ATF1 targets necessary for prostate cancer oncogenesis, and (3) define the CREB1/ATF1 signature in clinical human prostate cancer samples. Clinical Impact: We anticipate that our research will help all PCa patients by providing them with information about the aggressiveness of their disease at the time of diagnosis. This will let those with indolent disease know they do not have to pursue aggressive treatments, while ensuring those with lethal disease that aggressive treatment is essential. This will significantly reduce the clinical burden of overtreatment. There is some risk in that we don t know whether the targets we are proposing will prove to be the best or even useful for predicting disease aggressiveness. But if we find there is a high reproducible predictability associated with our targets, then we will know it very quickly (by the end of the study) and can thus move forward with developing a screen. Unique Contributions: This study will make several new contributions to PCa research. First, our special prostate differentiation model makes us uniquely poised to identify how human, as opposed to mouse, prostate cells make cell fate decisions an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710570
Entities
People
- Cynthia Miranti
Organizations
- United States Army
- University of Arizona