# Multifaceted integration for estrogen receptor

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $60,950

## 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:** 10581737
- **Project number:** 3R01GM114056-06A1S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Sichun Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $60,950
- **Award type:** 3
- **Project period:** 2015-08-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10581737

## Citation

> US National Institutes of Health, RePORTER application 10581737, Multifaceted integration for estrogen receptor (3R01GM114056-06A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10581737. Licensed CC0.

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