# Estrogen receptor mediated reprogramming of prostate in BPH

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $504,821

## Abstract

ESTROGEN RECEPTOR MEDIATED REPROGRAMMING OF THE PROSTATE IN BPH
Paul S. Cooke and Gail S Prins, Multi-PIs
Abstract
 Exposure to estrogens during critical developmental periods can permanently reprogram the prostate
gland, resulting in growth abnormalities in adult life that include stromal and epithelial hyperplasia, benign
adenomas and chronic prostatitis. As such, we propose that early-life estrogenic exposures may be a
predisposing factor for benign prostatic hyperplasia (BPH) in aging males. Past work has established that
epigenetic modifications underpin developmental reprogramming of the prostate; however, the pathways that
lead to this epigenomic reorganization are unclear. We previously showed that estrogen receptor 1 (ESR1;
also known as ERα) is essential and sufficient for this reprogramming; however, distinct signaling pathways
initiated through membrane ESR1 (mESR1) or nuclear ESR1 (nESR1) actions have not been clarified. Our
new published and preliminary data now reveal essential roles for mESR1 in normal male reproductive
development and fertility, as well as the normal prostatic response to developmental estrogenization. Further, a
recent report found that important epigenetic changes that could lead to hyperresponsivity of certain genes
involved in growth and cell proliferation can be initiated through mESR1 signaling cascades in the developing
prostate gland. In this context, the goals of the proposed research are to delineate relative roles of mESR1 and
nESR1 in mediating developmental estrogen reprogramming and to identify “nongenomic” pathways utilized by
mESR1 to reprogram epigenomic memory within the gland, including prostate epithelial stem cells. Herein, we
will take an innovative approach to directly interrogate mESR1 and nESR1 actions by utilizing newly developed
knock-in mouse models that express nESR1 normally but lack mESR1 signaling (nuclear-only ESR1 mouse;
NOER) or that express mESR1 and its downstream signaling pathways but lack nESR1 (H2NES mouse).
These powerful and unique new models allow us to take a direct experimental approach to tease out the
specific role(s) for ESR1 in each compartment and their downstream effectors on epigenetic imprinting in the
prostate, which has previously not been possible. Three Specific Aims are proposed to accomplish these
goals. Aim 1: Establish whether mESR1 is necessary and/or sufficient for estrogen-driven developmental
prostate reprogramming. Aim 2: Identify signaling cascades involved in estrogen-induced epigenetic imprinting.
Aim 3: Elucidate the roles of mESR1 and nESR1 in reprogramming prostate stem/progenitor cells. The
proposed studies will fill knowledge gaps on the differential roles of mESR1 and nESR1 in prostate
development and broaden the mechanistic basis for estrogenic imprinting in the prostate. Together, the results
will provide new and clinically relevant insights regarding the role of estrogen signaling through both mESR1
and nESR1 in driving BPH and inform ...

## Key facts

- **NIH application ID:** 10224181
- **Project number:** 5R01DK117633-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Paul S. Cooke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $504,821
- **Award type:** 5
- **Project period:** 2018-09-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224181

## Citation

> US National Institutes of Health, RePORTER application 10224181, Estrogen receptor mediated reprogramming of prostate in BPH (5R01DK117633-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224181. Licensed CC0.

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