Preliminary Data: Half of all prostate cancers are caused by a gene-fusion that enables androgens to drive expression of the normally silent ETS transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported rare but recurrent point mutations and narrow focal deletions in the ETS repressor ERF. Here we show these ERF mutations cause decreased protein stability and are mostly exclusive from those with ERG fusions. ERF loss recapitulates the morphologic and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor (AR) transcriptional repertoire, and ERF has tumor suppressor activity in the same genetic background of PTEN loss that yields oncogenic activity by ERG. In the more common situation of a tumor possessing wild-type ERF, ChIP-seq studies indicate that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites in both normal and cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumor growth and ERF loss rescues ERG-positive prostate cancer cells from ERG dependency. This preliminary data is described in the applicant's first author manuscript in press at Nature. Rationale and Aims: We have now discovered that loss of function mutations and copy number deletions in `negative' ETS factors are commonplace in prostate cancer. I) We aim to determine the collective importance of negative ETS factor (ETV3 and ETV6) mutations in prostate cancer. II) We aim to determine whether ERF negative regulates AR by affecting AR's ability to bind DNA or by actively repressing its function. III) We believe that negative ETS factors are continually outcompeting positive ETS factors, even in normal prostate. We seek to identify these endogenous positive ETS factors. Impact: The results of these studies will describe how ETS factors coordinate within normal prostate cells. They may also shed light on why TMPRSS2-ERG is a poor clinical biomarker. Thirdly, they may explain the pathogenesis of the half of prostate cancers that lack TMPRSS2-ERG. And finally, they may shed light on the oncogenesis of other ETS-dependent cancers such as leukemias and sarcomas. Applicant and career development: The applicant, Dr. Rohit Bose, is performing his postdoctoral work in Charles Sawyers laboratory and is also an Instructor in the Genitourinary Service at Memorial Sloan Kettering Cancer Center (MSKCC). He has outlined a 5-year career plan that builds upon his research background studying molecular mechanisms of prostate oncogenesis and his clinical training in medical oncology. Dr. Bose will conduct the proposed research under the mentorship of Dr. Charles Sawyers, an internationally recognized expert in prostate cancer biology and targeted therapy development, with a strong track record of training successful physician scientists. MSKCC provides the ideal institutional environment for Dr. Bose to embark on the proposed research program and transition to a position as an independent academic investigator with his own laboratory and R01 funding.
The ERF protein usually functions as a `brake' on cell growth, but in 4% of prostate cancers, it acquires a mutation and loses its function, thereby driving the development of prostate cancer. Leading from this discovery, we have gone on to show that in 50% of prostate cancers, ERF loses its function by being outcompeted by a different protein, ERG, which is an `accelerator' on growth. In this proposal, we investigate just how widespread is this competition between `brakes' and `accelerators' among a family of proteins that cause prostate cancer, and exactly how they regulate the testosterone receptor, which is the primary drug target for treatment.