Overexpression of ETS family transcription factors (ERG, ETV1, ETV4, ETV5, FLI1) through genomic fusion is the most common molecular aberration in prostate cancer, occurring in half of all cases. The TMPRSS2-ERG fusion that places ERG under the androgen-regulated TMRPSS2 gene is the predominant fusion, found in 80- 90% of all ETS-positive cancers. The molecular mechanisms underlying ETS-mediated oncogenesis in prostate cancer remain elusive. In genetically engineered mouse models (GEMM), ERG expression alone is not sufficient to drive prostate tumorigenesis. However, it causes dramatic reprogramming of the androgen receptor genomic binding profile (AR cistrome). In conjunction with Pten loss, ERG promotes tumorigenesis as well as significant transcriptome changes and confers resistance to combined PI3K/AR pathway inhibition, a therapy that is highly effective in prostate tumors initiated by Pten loss alone. These findings underscore the important biology that underlies interactions between AR, ERG and PTEN not only in mouse and human prostate cancer models, but also in human prostate cancer clinical specimens where aberrations in these pathways are also highly linked. This R01 project will examine the molecular details underlying these interactions by: (i) determining the mechanisms by which ERG reprograms the AR cistrome, creating a state where the prostate is primed to respond to upstream signals (e.g., Pten loss), (ii) elucidating the signaling events downstream of Pten loss that activate ERG-mediated transcription modules in mouse and human prostate tissue and (iii) determining the impact of ERG on response to AR pathway inhibition. To achieve these Aims, we will make extensive use of new mouse and human prostate organoid technology, generated by our group that enables precise mechanistic analysis of defined populations of luminal and basal prostate epithelial cells in ways not previously possible. We will leverage innovation approached in computational systems biology (Andrea Califano, Columbia) to predict candidate signaling pathways and transcription factors modulated by Pten loss that cooperate with ERG.

Public Health Relevance

Over half of prostate cancer cases are caused by chromosome translocations that result in aberrant expression of the ERG transcription factor. This project will shed light on the molecular mechanisms by which ERG causes prostate cancer and the impact of ERG on response to therapies directed against the androgen receptor, the common form of treatment for metastatic prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA193837-01
Application #
8863630
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$487,103
Indirect Cost
$198,049
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Xie, Yuanyuan; Cao, Zhen; Wong, Elissa Wp et al. (2018) COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors. J Clin Invest 128:1442-1457
Moore, Amanda R; Ran, Leili; Guan, Youxin et al. (2018) GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma. Cell Rep 22:2455-2468
Chen, Yu; Chi, Ping (2018) Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. J Hematol Oncol 11:78
Ran, Leili; Chen, Yuedan; Sher, Jessica et al. (2018) FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor. Cancer Discov 8:234-251
Abida, Wassim; Sawyers, Charles L (2018) Targeting DNA Repair in Prostate Cancer. J Clin Oncol 36:1017-1019
Hieronymus, Haley; Murali, Rajmohan; Tin, Amy et al. (2018) Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. Elife 7:
Shoag, Jonathan; Liu, Deli; Blattner, Mirjam et al. (2018) SPOP mutation drives prostate neoplasia without stabilizing oncogenic transcription factor ERG. J Clin Invest 128:381-386
Shukla, Shipra; Cyrta, Joanna; Murphy, Devan A et al. (2017) Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance. Cancer Cell 32:792-806.e7
Viswanathan, Vasanthi S; Ryan, Matthew J; Dhruv, Harshil D et al. (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453-457
Shah, Neel; Wang, Ping; Wongvipat, John et al. (2017) Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife 6:

Showing the most recent 10 out of 32 publications