# Multifaceted integration for estrogen receptor

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $347,760

## Abstract

Abstract
 Human estrogen receptor alpha (ERα) is a molecular driver of hormone-responsive cell
proliferation in breast cancer. Acquired ERα mutations—Y537S and D538G being the two most
commonly found—represent a newly recognized mechanism of drug resistance due to their
constitutive transcription activity. Our preliminary data and recently published reports indicate that
these drug-resistant mutants are non-conventional therapeutic targets for small molecule binding
to modulate their activity and inhibit cell proliferation. However, the mechanisms by which drug-
resistant mutations act on the receptor to regulate hormonal signaling and the extent to which
small molecule inhibitors bind the receptor for intervention are not yet known.
 The ERα harbors two major functional entities, i.e., the DNA-binding domain (DBD) and
the ligand-binding domain (LBD). We recently reported the multi-domain assembly and revealed
the mode of interactions between these two domains, through a previously uncharacterized
domain-bridging interface. Specifically, mutations at the domain-interface prevent the two
domains from communicating and inhibit ERα activity, highlighting the modulation of the domain-
interface as an “allosteric” channel with loss/gain of receptor function. This functional significance
raises the questions of (a) whether the drug-resistant mutations alter the domain-domain
assembly and the mode of DBD-LBD interactions, and (b) whether/how the domain-bridging
interface can be targeted by small molecules to disrupt receptor activity. Our preliminary studies
show that a repurposed small molecule binds the receptor via the domain-interface and inhibits
ERα-mediated cellular function. Based on these findings and other preliminary data, we
hypothesize that how the ERα domains interact with one another is influenced by these drug-
resistant mutations and this domain-domain interaction is critical for small molecule binding to
alter receptor function. To test this hypothesis, we will characterize the multi-domain assemblies
of disease-resistant mutants (Y537S/D538G) and examine the molecular and functional
correlation of inhibitor-receptor binding. In contrast to the hormone-binding pocket where all
current drugs bind, this study will provide novel insights into the ERα domain-interface as a new
target site for small molecule binding, and ultimately offer a much-needed molecular
understanding of ER-positive breast cancer therapy resistance.

## Key facts

- **NIH application ID:** 10909136
- **Project number:** 5R01GM114056-09
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Sichun Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $347,760
- **Award type:** 5
- **Project period:** 2015-08-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909136

## Citation

> US National Institutes of Health, RePORTER application 10909136, Multifaceted integration for estrogen receptor (5R01GM114056-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10909136. Licensed CC0.

---

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