# Molecular Function and Mechanism of ARID4B in ERalpha Signaling and Breast Cancer

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2022 · $407,813

## Abstract

Project Summary/Abstract
Over 70% of breast cancer are ERα+ and endocrine therapy is the standard treatment for these patients.
Unfortunately, resistance to endocrine therapy develops over time and remains a major problem. The cause for
resistance is not fully understood, but aberrant ERα activation is an underlying factor. Therefore, identifying new
component of the ERα signaling and understanding its role in breast cancer holds a great promise for treatment
of ERα+ cancer and will particularly benefit patients with advanced and metastatic tumors that are refractory to
current endocrine therapies. Our preliminary results showed that chromatin remodeling protein AT-rich
interaction domain 4B (ARID4B) is an essential transcription co-activator (not a co-repressor) for ERα and
mammary gland-specific ablation of Arid4b inhibits tumorigenesis. Analyses of large-scale genomic datasets
(TCGA and other breast cancer cohorts), genome-wide transcriptome, and IHC analyses showed that ARID4B
is amplified and its expression elevated in ERα+ breast cancer. Interestingly, high ARID4B expression in ERα+
(but not ERα-) breast cancers is associated with increased risk of cancer recurrence and decreased survival,
suggesting that ARID4B is involved in the cancer development and progression to therapy resistance. To gain
mechanistic insight into its function, preliminary results revealed that ARID4B is recruited to the promoters of
ERα target genes that are far away from the identified ERα-bound enhancers. In addition, DHX9 was identified
as a novel ARID4B-interacting protein and is involved in ERα activation. DHX9 is an NTP-dependent helicase
capable of resolving transcription-coupled ‘R-loops’ that is inhibitory to productive transcription. Based on these
findings, our central hypothesis is that ARID4B activates ERα signaling to promote tumorigenesis and
endocrine therapy resistance by: (1) mediating promoter-enhancer looping via interaction with ERα and (2) by
recruiting DHX9 to resolve the transcription-coupled R-loops on promoters and enhancers to promote productive
transcription. In Aim 1, the in vivo function of ARID4B in tumor initiation, cancer growth, and endocrine therapy
resistance will be investigated using several breast cancer cells in tumor xenograft models, patient-derived
resistant tumors in PDX, and a newly generated ARID4B knock-in mouse model. In Aim 2, we will investigate
how ARID4B-mediated enhancer-promoter looping regulates ERα activation and identify the important functional
domain(s) on ARID4B to provide in-depth understanding of ARID4B-ERα and ARID4B-DHX9 interactions.
Furthermore, we will investigate whether resolution of “R-loops” on the promoter and enhancer by DHX9 is
required for the activation of ERα. Finally, we will demonstrate that targeting the ARID4B-DHX9 axis by
suppressing DHX9 expression or activity inhibits tumorigenesis and resistance to antiestrogens. Our study will
fill the crucial gap in understanding the function and m...

## Key facts

- **NIH application ID:** 10522358
- **Project number:** 1R01CA266432-01A1
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Ray-Chang Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $407,813
- **Award type:** 1
- **Project period:** 2022-08-02 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522358

## Citation

> US National Institutes of Health, RePORTER application 10522358, Molecular Function and Mechanism of ARID4B in ERalpha Signaling and Breast Cancer (1R01CA266432-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10522358. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*