# Targeting Mechanisms of Endocrine Resistance in Breast Cancer

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $357,880

## Abstract

Project Summary/Abstract
Endocrine therapies that inhibit estrogen receptor (ER) signaling are the mainstay of the systemic treatment of
ER+ breast cancers. These therapies consist of approaches to reduce estrogen levels including luteinizing
hormone-releasing hormone (LHRH) agonists in premenopausal women and aromatase inhibitors (AI) in
postmenopausal women, and direct ER antagonists such as tamoxifen and fulvestrant. In the advanced disease
setting, however, endocrine therapy-resistant cancers almost invariably emerge and are the major cause of
breast cancer deaths. Multiple genetic and epigenetic mechanisms have been proposed to explain the
emergence of endocrine therapy resistance. Several groups including our own have characterized mutations in
the ER gene (ESR1) itself as a mechanism of resistance in approximately 20-30% of cases. We have developed
cell line and patient-derived xenograft (PDX) models of endocrine therapy-resistant ER+ breast cancer driven by
these ESR1 mutations and have found that these mutations exhibit both ligand-independent functions that mimic
estradiol-bound wild-type ER as well as allele-specific neomorphic properties that confer on ER novel signaling
functions that promote a pro-metastatic EMT-like phenotype. In addition, using genome-wide CRISPR screens,
we have identified genes essential for the growth of ER+ breast cancers. Importantly, we have also identified
genes whose loss confers endocrine therapy resistance in the setting of the wild-type ER, including NF1, TSC1/2,
PTEN and CSK. In these studies, we have found that loss of CSK leads to activation of SRC-family kinases
(SFK), thereby promoting estrogen-independent growth and a pro-metastatic cancer cell phenotype. Notably,
expression of CSK is regulated by estrogen through binding of ER directly to a transcriptional enhancer in the
CSK gene. This reveals the existence of an estrogen-induced negative feedback loop that constrains the growth
of ER+ tumors thereby limiting the efficacy of current therapies that target ER. The existence of this feedback
loop suggests the provocative hypothesis that current endocrine therapies may themselves promote a pro-
metastatic phenotype. Consistent with the overarching theme of this program to define new therapeutic
vulnerabilities, we will study how genetic and epigenetic heterogeneity impact the development of resistance to
endocrine therapy. Success of this project will allow the development integrative models of the
mechanisms of endocrine therapy resistance that include the effect of tumor heterogeneity that can be
used to predict effective new therapeutic targets and will allow the investigation of the link between
endocrine therapy resistance, endocrine therapy and metastasis.

## Key facts

- **NIH application ID:** 10023398
- **Project number:** 1P01CA250959-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** MYLES A BROWN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,880
- **Award type:** 1
- **Project period:** 2020-09-11 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023398

## Citation

> US National Institutes of Health, RePORTER application 10023398, Targeting Mechanisms of Endocrine Resistance in Breast Cancer (1P01CA250959-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10023398. Licensed CC0.

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