# Role of ETS factors in specifying prostate luminal cell identity and androgen receptor dependence

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $462,155

## Abstract

ABSTRACT
ETS family protein alterations (primarily ERG translocations) are present in >50% of human prostate cancers
in Western men. We were the first to develop a robust GEM model of ERG-driven prostate cancer, revealing
enhanced luminal differentiation and an expanded androgen receptor (AR) cistrome in tumors, suggesting a
novel mechanism for ERG oncogenicity via chromatin programming (Chen, 2013). We and others
subsequently established that ERG activates a luminal differentiation program in prostate organoids, human
prostate cell lines and, by computational analysis of prostate cancer genomes, in clinical samples (Blee et al.,
2018; Kron et al., 2017; Li et al., 2020b). Other ETS gain-of-function alterations e.g. ETV4 translocations (Li et
al., 2020a) and ETS loss-of-function alterations e.g. ERF repressor mutations/deletions (Bose et al., 2017) also
show this phenotype, as does FOXA1 (also amplified or mutated in prostate cancer) but with a contracted AR
cistrome (Adams et al., 2019). Having demonstrated that luminal differentiation is a primary feature of multiple
oncogenic ETS proteins (and FOXA1), our major goal during the next funding cycle is to understand how ERG
activates this differentiation program and how this program results in an oncogenic phenotype. We will pursue
three parallel lines of investigation. First, from our biochemical studies using purified full-length proteins and
various DNA templates, we find that that ERG (and other ETS factors) cooperatively enhance AR DNA binding
through allosteric effects via direct protein-protein interaction; biologically, this broadens the AR cistrome to
include novel AR binding sites (Wasmuth et al., 2020). Aim 1 will expand this analysis to assess the role of
FOXA1 on AR/ERG interactions. Second, we have built genetically defined prostate organoid models that
recapitulate the luminal differentiation effect of ERG within a precisely defined time course. Using this system,
we identified epigenetic changes that silence transcription of the basal epithelial master regulator p63, likely
explaining the reduction in basal cells. Aim 2 will use lineage tracing, single cell analysis, and CRISPR
screening to further elucidate how ERG expands the number of luminal cells and initiates oncogenic
transformation. Third, we showed that another oncogenic ETS protein (ETV4) also drives luminal differentiation
and is sufficient, alone, to initiate prostatic intraepithelial neoplasia (PIN). Remarkably, these luminal epithelial
cells acquire exquisite dependence on AR for survival (in contrast to normal luminal epithelial cells) and
consequently display enhanced sensitivity to androgen deprivation therapy (ADT). Aim 3 will explore
mechanisms underlying this shift to cell-intrinsic AR dependence by examining changes in the AR cistrome
and transcriptome following luminal-specific AR ablation (by genetic deletion) versus systemic androgen
deprivation through surgical castration (impairs AR function in prostate st...

## Key facts

- **NIH application ID:** 10348178
- **Project number:** 5R01CA193837-07
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** CHARLES L. SAWYERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $462,155
- **Award type:** 5
- **Project period:** 2015-04-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348178

## Citation

> US National Institutes of Health, RePORTER application 10348178, Role of ETS factors in specifying prostate luminal cell identity and androgen receptor dependence (5R01CA193837-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348178. Licensed CC0.

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