# Functional Significance of individual p53 mutations in determining the role of estrogen receptor beta in triple negative breast cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2022 · $599,304

## Abstract

Triple negative breast cancers (TNBCs) do not express estrogen receptor-α (ERα), progesterone receptor (PR),
or human epidermal growth factor receptor 2 (HER2), and therefore, none of the targeted drugs currently in use
for breast cancer are effective against them. Approximately 60-80% of TNBCs express estrogen receptor-β
(ERβ). However, pro- versus anti-tumorigenic capabilities of ERβ remains controversial. Another key molecular
characteristic of TNBC is the high frequency (80%) of p53 mutation. In addition to losing tumor suppressor
properties and exerting dominant-negative regulation over any remaining wild type p53 (WTp53), mutant p53
also acquires oncogenic gain-of-function. Increasing evidence suggests that not all mutant p53s function
similarly. Although ERβ and p53 have been implicated in TNBC pathology, whether p53 has a role in the pro-
versus anti-proliferative functional duality of ERβ remains an open question. The long-term goal is to understand
and exploit the role of ERβ-p53 crosstalk in breast cancer for the development of better therapeutic strategies.
The objective is to study how specific mutations in p53 impinges upon ERβ function in TNBC, with the prediction
that specific p53 mutation will determine its role in the ERβ-mutant p53-p73 signaling axis impacting multiple
aspects of tumor progression and metastasis. The hypothesis is that ERβ binds to and inhibits both WTp53 and
mutant p53, leading to opposite effects on progression and therapeutic response of TNBC to agents such as
Tamoxifen (Tam). The rationale for the proposed research is that understanding how ERβ elicits opposite
functions in a p53 status-dependent manner will be critical to stratify TNBC patients to repurpose established
therapeutic agents such as Tam to treat large percentage of TNBC patients. The specific aims are: (1 Determine
the interaction of different p53 mutants with p73 and ERβ in TNBC cells; (2) Analyze the differential effects of
p53 mutants on tumor progression, metastasis and therapeutic response in vivo; and (3) Evaluate the clinical
significance of the ERβ-p53-p73 signaling axis. In specific aim 1, Isogenic TNBC cells expressing different
combinations of ERβ and WT and p53 mutants generated using CRISPR technology and shRNA-mediated
conditional knockdown will be used for analyzing the mechanisms underlying the interaction and its impact on
cellular functions in vitro and tumor progression in vivo. In specific aim 2, the effect of different p53 mutations on
tumor growth and metastasis will be analyzed in vivo. The clinical relevance of these studies will be evaluated
using well-characterized patient derived xenografts (PDXs); patient tumor-derived organoids (PDOs); and patient
tumor tissues with linked clinical database (specific aim 3). The contribution of this research is expected to be
better understanding of the mechanisms by which ERβ-p53-p73 axis in the context of different p53 mutations
affects the disease progression and therapeutic res...

## Key facts

- **NIH application ID:** 10359129
- **Project number:** 5R01CA251545-02
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** GOKUL M. DAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $599,304
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359129

## Citation

> US National Institutes of Health, RePORTER application 10359129, Functional Significance of individual p53 mutations in determining the role of estrogen receptor beta in triple negative breast cancer (5R01CA251545-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10359129. Licensed CC0.

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