# Impact of aging on prostate cancer with TMPRSS2-ETS gene fusion

> **NIH NIH UH3** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $150,000

## Abstract

This proposed project will test a central hypothesis that aged milieu of the organism has an impact on the
pathobiology of prostate cancer. Prostate cancer is one of the human cancer types most notably associated
with advanced age. In fact, old age is thought as the most significant risk factor for developing prostate
cancer in men. Several aging-associated molecular and cellular changes, such as changes in the prostatic
microenvironment (e.g., chronic inflammation, changes in collagen and smooth muscle cells in the stroma),
oxidative stress, genomic damage due to androgenic stimulation, changes in the hormone milieu (e.g.,
estrogen/androgen ratio), and changes in metabolism, etc., may contribute to prostate tumorigenesis.
Among somatic mutations in prostate cancers, gene fusions involving ETS family transcription factors
(mainly ERG, followed by ETV1) have been found in ~50% of human prostate cancer cases. The majority of
these gene fusions are formed by joining the control region of an androgen (and estrogen)-responsive gene,
TMPRSS2, to the coding region of ERG or ETV1. Collectively, these ETS fusions represent an early event
in prostate tumorigenesis. Several Cre/loxP-based inducible knockin mouse models were generated by us
to recapitulate the three major types of TMPRSS2-ETS fusions found in patients, including TMPRSS2-ERG
fusion with an interstitial deletion between TMPRSS2 and ERG loci (both genes are located on human
chromosome 21 and are ~3Mb apart), TMPRSS2-ERG fusion without deletion, and TMPRSS2-ETV1 fusion.
Previous studies using these models showed that while neither of the Tmprss2-ETS fusions alone was
sufficient to initiate prostate tumorigenesis, they could all cooperate with Pten-loss to drive prostate cancer
progression, suggesting these fusions sensitize prostate cells for cooperation with additional oncogenic
events during prostate tumorigenesis. As these findings were made in young mice, it is hypothesized that in
aged mice, aging-associated molecular and cellular changes may cooperate with TMPRSS2-ETS fusions,
leading to prostate cancer initiation and/or progression. To test this hypothesis, a CreER knockin (to the
constitutive Rosa26 locus) mouse model (R26-CreER) will be used to control activation of Tmprss2-ETS
knockin alleles, either alone or together with inactivation of one copy of Pten, in prostate cells, by
administration of tamoxifen to either aged (24 months) or matched young (4 months) male mice. The
induced mice will be followed for up to one year to determine the incidence, kinetics, grade and pathology
[e.g., prostatic intraepithelial neoplasia (PIN) or invasive cancer] of prostate lesions. A comparison of these
in the aged versus young cohorts would reveal aging-associated changes and whether such changes
cooperate with Tmprss2-ETS fusions, or with Tmprss2-ETS fusions plus Pten-loss to drive prostate cancer
development, and whether old mice represent a better model for studying prostate cancer.

## Key facts

- **NIH application ID:** 10007618
- **Project number:** 5UH3CA213392-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Zhe Li
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $150,000
- **Award type:** 5
- **Project period:** 2016-09-16 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007618

## Citation

> US National Institutes of Health, RePORTER application 10007618, Impact of aging on prostate cancer with TMPRSS2-ETS gene fusion (5UH3CA213392-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10007618. Licensed CC0.

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