The most common alterations of the prostate cancer genome are chromosomal rearrangements that result in aberrant expression of an ETS family transcription factor that is not normally expressed in prostate cells. Expression of these factors, including ERG, ETV1, and ETV4, in prostate cells is oncogenic. However, there are many other ETS factors present in normal prostate that are important for normal functions, and can even be tumor suppressors. Thus, to devise therapies to target ETS factors in prostate cancer, it is critical to understand specific functional mechanisms specific to oncogenic family members. Preliminary data from the applicants' laboratory supports the central hypothesis of this proposal, which proposes that all oncogenic ETS family members activate a similar gene expression program through specific mechanisms that are not used by non-oncogenic ETS proteins. The following three specific aims will be used to identify specific functions of oncogenic ETS proteins: 1) Determine the common transactivation mechanism of ETS factors that drive prostate cancer; 2) Identify mechanisms used by signaling pathways to regulate ERG function in prostate cells; and 3) Determine how oncogenic ETS factors function in prostate cells within the context of the ETS family.
These aims are guided by strong preliminary data including the identification of proteins that specifically associate with oncogenic ETS proteins and not with non-oncogenic ETS proteins. In vitro and in vivo assays will test the importance of these interactions, and mechanistic details will be determined using biochemical and genome-wide mapping techniques. Completion of these studies will yield the first understanding of functional mechanisms unique to oncogenic ETS proteins and provide important new molecular targets for pharmacological strategies to prevent both the growth and progression of cancer.

Public Health Relevance

Mutations that lead to the aberrant function of an ETS transcription factor are among the most common causes of cancer. However, the reason that some ETS proteins promote cancer, while others inhibit cancer, is unknown. The identification of molecular mechanisms specific to oncogenic ETS protein function will allow the development of novel strategies for cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA204121-02
Application #
9485320
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Witkin, Keren L
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202