# Contribution of ERa/PR Crosstalk to Endocrine Therapy Resistance in the Context of ERa-Y537S

> **NIH NIH F31** · UNIVERSITY OF CHICAGO · 2021 · $46,036

## Abstract

PROJECT SUMMARY/ABSTRACT
Half of estrogen receptor (ERα)-positive breast cancer patients treated with endocrine therapies manifest intrinsic
or acquired therapy resistance. One-third of these patients present with metastatic tumors containing ERα Y537S
mutations. This mutation results in constitutive activity of ERα and altered ERα-associated gene expression.
Previous research suggests that ERα and the progesterone receptor (PR) engage in complex interactions
involving reciprocal regulation of ERα and PR transcription factor activity known as ERα/PR crosstalk. Thus,
there may be therapeutic value in targeting both nuclear receptors simultaneously in ERα/PR-positive breast
cancers. However, preliminary data suggests that ERα/PR crosstalk is altered in the context of ERα Y537S,
likely contributing to therapy resistance. Although the constitutive activity associated with ERα Y537S and the
efficacy of combined ERα/PR therapies have independently been assessed, there has yet to be characterization
of the effects of ERα Y537S on ERα/PR crosstalk or the specific effects of ERα/PR-targeted therapies on
ERα/PR crosstalk in the context of ERα Y537S. The objective of this proposal is to determine the effects of the
most commonly occurring, treatment-resistant ERα Y537S mutation on ERα/PR crosstalk and resultant
transcriptional activity, and to elucidate how this unique interaction leads to endocrine therapy resistance in ERα-
positive breast cancer. Previous research identified a synergistic effect of combined ERα/PR antagonism in ERα
WT cancer cells, where combined treatment results in tumor regression in vivo. Conversely, preliminary data
suggests that treatment of ERα Y537S tumors with combined ERα and PR antagonists results in significantly
increased tumor proliferation in vivo. As previous research has highlighted a significant alteration in gene
expression associated with ERα Y537S, it is likely that changes to both ERα- and PR-driven gene expression
drive the altered response to ERα and PR antagonists. My central hypothesis is that ERα Y537S alters the
transcription factor activity of ERα and PR, causing dysregulation of gene expression in SERM-resistant breast
cancer. This hypothesis will be assessed with the following Specific Aims:
 1. Determine how the activating ERα Y537S point mutation affects ERα transcriptional activity and alters
 ERα/PR crosstalk.
 2. Assess the efficacy of various selective estrogen and progesterone receptor modulators (SERMs and
 SPRMs) in treating patient-derived models of ERα Y537S tumors.
Understanding the role of ERα Y537S in altering gene expression and reducing the response to SERM and
SPRM treatment will provide understanding as to why these tumors are resistant to standard-of-care treatment
and will additionally suggest alternative targets for treatment.

## Key facts

- **NIH application ID:** 10153330
- **Project number:** 1F31CA257634-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Rosemary J Huggins
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153330

## Citation

> US National Institutes of Health, RePORTER application 10153330, Contribution of ERa/PR Crosstalk to Endocrine Therapy Resistance in the Context of ERa-Y537S (1F31CA257634-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10153330. Licensed CC0.

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