# A precision medicine basis for estrogen therapy for advanced breast cancer

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $398,676

## Abstract

Project Summary: It remains unknown why some estrogen receptor alpha (ER)-positive breast cancers are
sensitive to estrogen therapy while others are resistant, and strategies for effectively utilizing estrogen therapy
are not well-established. The long-term goal of this line of investigation is to maximize the clinical potential of
endocrine therapies for the management of ER+ breast cancer. The overall objective of this project is to define
the mechanism that controls cell fate in ER+ breast cancer in response to the estrogen 17b-estradiol. The
central hypothesis is that basal estrogen-independent ER transcriptional activity caused by ER amplification,
overexpression, or mutation sensitizes breast cancer cells to the cytotoxic effects of 17b-estradiol/ER-induced
DNA damage. The rationale for this project is that definition of (i) the mechanism underlying therapeutic
response to 17b-estradiol and (ii) tumor features that dictate response to 17b-estradiol will provide a precision
medicine basis for its use and offer strategies to enhance response. The central hypothesis will be tested by
pursuing three specific aims: (1) Determine how 17b-estradiol/ER-induced DNA damage and response control
cell fate; (2) Determine how inhibition of the DNA damage response affects sensitivity to 17b-estradiol; (3)
Define the role of ER (ESR1) mutations in dictating breast cancer response to 17b-estradiol. In the first aim,
the kinetics and spatiotemporal relationship of 17b-estradiol/ER-induced transcriptional activity, DNA damage,
and response will be measured in genetically engineered and estrogen-independent ER+ breast cancer cells.
These studies will provide a mechanistic basis for the cytotoxic effects of 17b-estradiol. The second aim will
use cell lines and patient-derived xenografts for measurement of the effects of 17b-estradiol in the context of
pharmacological inhibition of poly(ADP-ribose) polymerases 1/2 (PARP) as well as homologous recombination
deficiency. These studies will offer treatment strategies to enhance response to 17b-estradiol. In the third aim,
engineered cells and ESR1-mutant patient-derived xenografts will be used for measurement of 17b-estradiol-
induced changes in cell fate, tumor growth, and ER transcriptional activity. These studies will provide
understanding of how ESR1 mutations shape cancer cell response to 17b-estradiol and provide a mechanistic
basis to inform its clinical use. The proposed research is innovative because it implicates ER-induced DNA
damage in the mechanism of cytotoxicity induced by 17b-estradiol therapy, enabling the development of
strategies that target the DNA damage response for advanced ER+ breast cancer. Based on our clinical trial
findings, this project will test the innovative concept that ER mutations sensitize ER+ breast cancer cells to
17b-estradiol. The proposed research is significant because it will reveal the root cause of 17b-estradiol-
induced cytotoxicity in ER+ breast cancer, as well as expla...

## Key facts

- **NIH application ID:** 10444375
- **Project number:** 2R01CA200994-06
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Todd W. Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $398,676
- **Award type:** 2
- **Project period:** 2017-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444375

## Citation

> US National Institutes of Health, RePORTER application 10444375, A precision medicine basis for estrogen therapy for advanced breast cancer (2R01CA200994-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10444375. Licensed CC0.

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