# Estrogen Receptor Beta inhibits Nuclear Factor kappa B to suppress Triple Negative Breast Cancer

> **NIH NIH F31** · MAYO CLINIC ROCHESTER · 2020 · $37,080

## Abstract

PROJECT SUMMARY/ABSTRACT
Triple Negative Breast Cancer (TNBC) affects approximately 20% of breast cancer (BC) patients and is the
most aggressive sub-type of BC, in part due to the lack of therapeutic options available for patients. Our
laboratory has demonstrated that Estrogen Receptor Beta (ERβ) protein is detectable at moderate to high
levels in approximately 30% of TNBCs, and BC patients whose tumors retain ERβ expression have enhanced
therapeutic response, lower rates of breast cancer recurrence, and improved disease-free survival. In addition,
we have shown that activation of ERβ by estradiol (E2) decreases TNBC cell proliferation, invasion, and
migration, demonstrating that ERβ functions as a tumor suppressor and is a relevant and novel drug target. To
determine the mechanisms by which ERβ elicits its tumor suppressive effects, we have for the first time
elucidated the ERβ transcriptome and cistrome in TNBC cells. Through pathway analysis of our gene
expression studies, we identified the NFκB pathway as one of the most suppressed pathways in response to
ligand-mediated activation of ERβ. Among the most down-regulated genes following E2 treatment were
members of the interleukin (IL) family, which are known NFκB target genes. Chromatin Immunoprecipitation
followed by sequencing (ChIPseq) for ERβ in TNBC cells revealed that ERβ was not only associated with
EREs following E2 treatment, but was also enriched around NFκB binding sites. In fact, 12% of all ERβ binding
sites encode NFκB response elements. Using an NFκB reporter construct and gene expression studies, we
have shown that ligand-mediated activation of ERβ suppresses canonical NFκB signaling and blocks the
activating functions of TNFα. We have also shown that this suppression is a result of chromatin modification.
Suppression of NFκB signaling is known to inhibit proliferation and invasion of TNBC cells in vitro and
decreased expression of NFκB target genes is associated with improved survival of TNBC patients, yet direct
suppression of NFκB signaling has toxic side effects. However, we expect indirect or cell-specific blockade of
the NFκB pathway in TNBC patients would suppress tumor progression and improve outcomes. In light of
these observations and the known oncogenic properties of NFκB in TNBC, this proposal aims to address the
central hypothesis that ERβ elicits its tumor suppressive effects in TNBC by suppressing the NFκB signaling
pathway. In Specific Aim 1, we will determine the mechanisms by which ERβ suppresses NFκB signaling in
TNBC using multiple cell line model systems. In Specific Aim 2, we will utilize a novel ERβ transgenic mouse
model to determine the impact of ERβ expression and activation on TNBC progression and assess alterations
in NFκB signaling during this process. Additionally, we will employ patient-derived organoids to evaluate the
efficacy of ERβ targeted agents and its impact on NFκB signaling. Completion of these studies will define the
molecular mechanism...

## Key facts

- **NIH application ID:** 9841295
- **Project number:** 5F31CA228193-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Kirsten Aspros
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,080
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841295

## Citation

> US National Institutes of Health, RePORTER application 9841295, Estrogen Receptor Beta inhibits Nuclear Factor kappa B to suppress Triple Negative Breast Cancer (5F31CA228193-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9841295. Licensed CC0.

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