# Development of a clinically relevant mouse model of ER+ breast cancer

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $222,862

## Abstract

The purpose of this proposed R21 project is to develop and validate a novel, clinically relevant mouse model
for estrogen receptor-positive (ER+) breast cancer. Most human breast cancers are ER+ and are treated by
endocrine therapy. Current clinical challenges for treating ER+ breast cancer include: 1) some patients do not
respond to or develop resistance to endocrine therapy; 2) some patients eventually progress to ER+
metastatic breast cancer. Animal models that can faithfully recapitulate the biology of ER+ breast cancer are
essential for addressing these challenges in a preclinical setting. However, current in vivo models are
inadequate. It remains an unmet clinical need to more faithfully model ER+ breast cancer under the
physiological setting. The failure to model ER+ breast cancer faithfully in animals (e.g., mice) may be due to:
1) oncogenic events are not targeted to the correct cellular origin; 2) oncogenic mutations specifically
associated with human ER+ breast tumors are rarely modeled in mice. Taking these into consideration, we
recently developed a new mouse model for ER+ breast cancer based on a recurrent genetic mutation uniquely
found in human ER+ breast tumors, i.e., loss-of-function mutation or deletion of an estrogen/ER signaling-
related transcription factor gene, RUNX1. The model is based on intraductal injection of a Cre-expressing
adenovirus (Ad-Cre) under the control of the Keratin 8 promoter (Ad-K8-Cre) to female mice carrying
conditional knockout alleles of Runx1 and p53. Ad-K8-Cre-induced loss of RUNX1 and p53 in K8+ luminal
mammary epithelial cells (MECs) led to development of ER+ mammary tumors with hyperactive ribosome
biogenesis and immune responses, which are also observed in human RUNX1-deficient ER+ breast cancers.
However, since Ad-K8-Cre targets both ER+ and ER- luminal MECs and the resulting tumors exhibited
features of both ER+ and Claudin-low (i.e., tumor cells with mesenchymal-like appearance) cancers, it is
unclear whether the mixed tumor phenotype is due to their different cellular origins (e.g., ER+ vs. ER- luminal
MECs) and/or due to p53-loss (which promotes cell fate plasticity). We hypothesize that in order to make this
model more clinically relevant to human ER+ breast cancer, it can be further improved by inducing RUNX1-
loss and its cooperating oncogenic events (i.e., other than p53-loss) specifically in ER+ luminal MECs (i.e.,
the potential cellular origin of ER+ breast cancer). To address this, two Specific Aims are proposed. Aim 1
will focus on developing a new Ad-Cre tool to specifically target Cre expression to the ER+ luminal sublineage,
so that mammary tumorigenesis is initiated only from ER+ luminal cells. In Aim 2, we will test if oncogenic
events affecting the RB-E2F pathway (as hyperactive ribosome biogenesis may lead to ribosomal stress,
which may cause cell cycle arrest via this pathway) would cooperate with RUNX1-loss, leading to ER+
mammary tumors from luminal MECs. The successful d...

## Key facts

- **NIH application ID:** 10442604
- **Project number:** 5R21CA256468-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Zhe Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $222,862
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442604

## Citation

> US National Institutes of Health, RePORTER application 10442604, Development of a clinically relevant mouse model of ER+ breast cancer (5R21CA256468-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10442604. Licensed CC0.

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