# Roles of RORalpha in breast cancer development and progression

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $344,269

## Abstract

ABSTRACT
 Tumor has been described as the wounds that do not heal. The two share some common features, such as
loss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarity
induced macrophage infiltration. However, little is known of how disruption of epithelial cell polarity at early
stage of breast cancer development induces macrophage infiltration. We have identified the RAR-related
orphan nuclear receptor α (RORα) as a potent tumor suppressor by analyzing global gene expression profiles
in polarized and non-polarized mammary epithelial cells. Our recent findings show that RORα inhibits ROS
generation and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggest
that RORα is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found that
knockdown of RORα significantly induced ROS production in mammary epithelial cells. Reactive oxygen
species (ROS) are the driver of cancer progression and critical regulator of the NF-κB pathway. Based on
these novel findings, the central hypothesis of our proposal is that downregulation of RORα in non-polarized
breast cancer cells increased ROS generation in mitochondria, thereby inducing NF-κB and macrophage
infiltration. We integrate high-throughput metabolic analysis, a novel 3D co-culture system, and global gene
expression profiling to delineate mechanisms by which RORα inhibits ROS production and macrophage
infiltration. The long-term goal of this proposal is to define the impact of the RORα/ROS axis in mediating
mammary epithelial cell-macrophage crosstalk and in regulating breast cancer progression. We have proposed
following specific aims to test the hypothesis: Aim 1. To elucidate the molecular mechanisms by which RORα
reduces ROS levels and NF-κB activity in polarized mammary epithelial cells; Aim 2. To determine how
reduced RORα expression in non-polarized breast cancer cells induces macrophage infiltration and M2
polarization; Aim 3. Define the impact of RORα in suppressing breast cancer formation and metastasis. The
proposed study is high impact for its inherent scientific importance and its translational potential. This study will
elucidate the molecular mechanism by which disruption of tissue polarity induces macrophage
infiltration/differentiation. Determining roles of RORα in reducing ROS generation and inhibiting NF-κB
activation may identify a novel strategy to inhibit breast cancer development and progression.

## Key facts

- **NIH application ID:** 9957066
- **Project number:** 5R01CA215095-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Ren Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,269
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957066

## Citation

> US National Institutes of Health, RePORTER application 9957066, Roles of RORalpha in breast cancer development and progression (5R01CA215095-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957066. Licensed CC0.

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