# Project 2: Inflammation-Based Mechanisms of Hormone Therapy Resistance in Breast Cancer

> **NIH NIH P50** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $273,123

## Abstract

Project 2 Abstract
Breast cancer is the second leading cause of cancer mortality in women and nearly 75% of breast tumors
express estrogen receptor-α (ER) at the time of diagnosis. It is estimated that about 30-40% of ER+ breast
tumors become resistant to hormone therapy, either through de novo or acquired resistance. Recent evidence
suggests that inflammation plays a key role in promoting pathogenesis and acquired resistance to hormone
therapies, and is considered a risk factor for breast cancer. To this end, we and others have uncovered an
important mechanism linking inflammatory signaling to endocrine resistance in breast cancer through
interactions between the ER and NFB, via cytokine-induced phosphorylation of ER and direct modulation of the
ER pioneer factor FOXA1. This is important because greater than 80% of the lymph node metastases and 65–
70% of distant metastases arising from ER+ primary tumors retain ER expression at the time of relapse. Also,
inflammatory mediators, such as cytokines like the tumor necrosis factor alpha (TNF) or the master transcription
factor NFB and its upstream regulator IKK, are highly present in breast tumors and increase with tumor grade.
We will use ER+ breast cancer patient-derived xenografts (PDXs), and FACS isolated (EpCAM+/CD49f) ER+
luminal cells isolated from multiple patients, to understand how inflammatory signaling affects ER function. Our
hypothesis is that inflammatory signaling, driven by NFB and its upstream regulator IKK, leads to altered ER
function and target gene expression resulting in more aggressive tumors and an increased resistance to
endocrine therapy. First we will define the transcriptional and epigenetic response of the primary tumor
specimens to estrogen and cytokine induced inflammatory signaling using novel next-generation sequencing
technologies (such as GRO-seq, ATAC-seq and ChIP-seq) Then we will test if the primary human tumor
specimens, exhibit increased proliferation, invasion, metastasis and resistance to hormone therapy when
exposed to estrogen and inflammatory cytokines. We will also test if novel inhibitors of IKK/NFB will rescue
sensitivity to hormone therapy in the tumor specimens. Bioinformatic analysis of the data we generate across
many patients will allow us to identify biomarkers and/or gene signatures that are potentially prognostic of
patients that have worse outcomes on endocrine therapies and/or predictive of patients who may benefit from
inhibitors of NFB signaling. Listed below are the headings for our 3 specific aims:
Aim 1:Define the transcriptional changes and chromatin binding profiles of ER and NFB in primary human
tissues in response to E2 and proinflammatory cytokines.
Aim 2:Determine the biological consequences of inflammation-based modulation of ER function in breast tumors
Aim 3:Define prognostic signatures, identify biomarkers and measure prevalence of inflammation-based
modulation of ER function across patient samples.

## Key facts

- **NIH application ID:** 10244930
- **Project number:** 5P50CA058223-27
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Hector Luis Franco
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $273,123
- **Award type:** 5
- **Project period:** 1997-08-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10244930

## Citation

> US National Institutes of Health, RePORTER application 10244930, Project 2: Inflammation-Based Mechanisms of Hormone Therapy Resistance in Breast Cancer (5P50CA058223-27). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10244930. Licensed CC0.

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