DESCRIPTION (provided by applicant): Understanding the molecular mechanisms of the DNA damage response (DDR) is central to cancer research, as cancer is a consequence of abnormalities to DNA. Malfunction of the members of the DDR are found in majority, if not all, of human cancers. ERG is a transcription factor whose overexpression, as a result of chromosomal rearrangement is believed to play an important role in more than 50% of prostate cancers, myeloid leukemias and highly aggressive Ewing's sarcomas. Enigmatically, ERG appears to be lost in acute lymphoblastic leukemia, suggesting a tissue-specific role for ERG in tumorigenesis. This research will identify ERG as a DNA damage-responsive protein using in vitro and in vivo tools. Research will be conducted to investigate the possibility of ERG as a potential substrate for the ATM/ATR kinases following genotoxic stress. Another line of research, using in vitro and in vivo technology, will demonstrate that ERG participation in DDR is at least in part through transcritionally downregulating CHKI. Mice models, that were developed in our laboratory to specifically overexpress ERG in the prostate, will allow us to demonstrate that ERG overexpression is associated with CHK1 downregulation and subsequent genomic instability in vivo. Furthermore, mice models will be highly useful in achieving another aim of this proposal, which is to assess the role of ERG in DDR following induction of DNA damage in vivo. In addition, conditional ERG-knockout mice will be generated to further study the role of ERG in DDR and tumorigenesis using prostate cancer as a model. For in vitro studies, basic molecular and cellular biology approaches including western, northern and southern blot analysis, RT-PCR, ChIP assays, immunoprecipitation, immunofluorescence and immunohistochemistry analysis will be applied. Accomplishment of this proposal will provide us with new insights into the molecular mechanisms, by which elevated levels of ERG contribute to tumorigenesis. This knowledge is invaluable when designing novel and targeted therapeutic strategies in the fight against cancers that harbor excess amount of ERG. The fact that ERG is overexpressed in some cancers, but lost in others, further emphasizes the importance of understanding the mechanisms of action of ERG when developing cancer-specific therapy.
PUBLIC HEALTH RELEVANCE: An excess amount of ERG can frequently be found in human cancers including prostate, myeloid leukemias and highly aggressive Ewing's sarcoma. On the other hand, ERG is absent in acute lymphoblastic leukemia. This means the role of ERG in cancer is rather complex. Thus, it is essential to investigate how ERG levels contribute to cancer. The goal of this proposal is to better understand the ways ERG levels contribute to development of cancer. |