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

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2021 · $370,575

## Abstract

Breast tumors expressing estrogen receptor alpha (ER) but not HER2 (ER+/HER2-) account for the majority of
recurrences and deaths from breast cancer. In patients with early-stage disease, anti-estrogen therapies that
suppress ER activity prevent cancer recurrence, but ~33% of patients (~300,000 women diagnosed each year)
eventually develop recurrent disease. Advanced/metastatic breast cancer is managed with further anti-
estrogen therapies, targeted therapies, and DNA-damaging chemotherapies. Nearly all metastatic breast
cancers eventually become completely refractory to these therapies. Prior to the approval of tamoxifen,
estrogens were frequently used for the treatment of breast cancer. This may seem counterintuitive since we
now rely on anti-estrogens for disease management, but response rates to estrogens are similar to those of
anti-estrogens in the setting of advanced disease. Approximately 1/3 of anti-estrogen-resistant breast cancers
respond to estrogen therapy, translating into ~100,000 new patients each year who could benefit. Similarly,
some cancers respond to withdrawal of anti-estrogen therapy, which may be caused by ER reactivation. Breast
tumor responses to estrogen therapies and anti-estrogen withdrawal have been observed for >70 years, but
the lack of A) understanding of therapeutic mechanism(s), and B) criteria to identify patients likely to benefit
have hindered clinical use. To legitimize this inexpensive, widely accessible, time-tested, relatively safe and
tolerable treatment option, and to provide a precision medicine basis to limit its use to patients with cancers
likely to respond, the following critical issues need to be addressed: 1) understanding the mechanism(s)
underlying sensitivity of anti-estrogen-resistant breast cancers to estrogen therapy and anti-estrogen
withdrawal; 2) identifying tumor markers that predict benefit from ER reactivation therapy; 3) identifying
strategies to enhance response; 4) understanding the dynamics of therapeutic response/resistance. We
hypothesize that during adaptation to anti-estrogens and estrogen deprivation, ER+ breast cancer cells acquire
molecular changes that render estrogen-dependent ER reactivation proteotoxic and deleterious. We will test
this hypothesis through the following Specific Aims: 1) Determine whether a finite window of ER transcriptional
activation promotes growth of breast cancer cells, and how this window shifts with acquisition of anti-estrogen
resistance; 2) Determine how ER reactivation elicits proteotoxic stress-dependent cell death; 3) Determine the
optimal dose, duration, and mechanisms of escape from 17b-estradiol therapy in anti-estrogen-resistant breast
tumors; 4) Identify baseline and pharmacodynamic biomarkers that predict response to 17b-estradiol therapy in
patients with anti-estrogen-resistant breast cancer.

## Key facts

- **NIH application ID:** 10125111
- **Project number:** 5R01CA200994-05
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Todd W. Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,575
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125111

## Citation

> US National Institutes of Health, RePORTER application 10125111, A precision medicine basis for estrogen therapy for advanced breast cancer (5R01CA200994-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10125111. Licensed CC0.

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