Emergence of ETS transcription factors as diagnostic tools and therapeutic targets in prostate cancer

Abstract

The discovery of chromosomal translocations in prostate cancer has greatly enhanced our understanding of prostate cancer biology. Genomic rearrangements involving the ETS family of transcription factors are estimated to be present in 50-70% of prostate cancer cases. These rearrangements fuse the ETS factors with promoters of genes that are androgen regulated. Thus, the expression of ETS factors, such as ERG, ETV1, ETV4 and ETV5, is mediated by androgen. In-vitro and in-vivo studies suggest that overexpression of ETS proteins increase cell proliferation and confer an invasive phenotype to prostate cancer cells. Epidemiological studies demonstrate that ETS-fusion positive patients exhibit tumors corresponding to a more advanced disease. The ability of ETS factors to serve as markers for screening and diagnosing prostate cancer patients is being investigated, and the results have been largely positive to date. Additionally, ETS factors present an excellent opportunity as therapeutic targets and several strategies have been devised to directly target ETS proteins or their binding partners and downstream effectors.

Keywords: ETS; ETV1; Prostate cancer; TMPRSS2-ERG; chromosomal translocation; transcription factor.

Figure 1

Chromosomal rearrangements involving the ETS family of transcription factors result in truncated ETS proteins that are fused to androgen regulated gene promoters. This lead to androgen regulation of ETS protein expression. ETS proteins regulate the expression of a subset of genes that increase cell proliferation, invasion and metastasis. Inhibition of ETS proteins provide a promising therapeutic target for the treatment of prostate cancer and inhibition of prostate cancer metastasis. These proteins can be targeted by blocking their binding to DNA or inhibiting their interaction with associated cofactors.