# Manipulating normal estrogen physiology as a therapeutic approach in cancer

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $514,902

## Abstract

Background: Cancers of the reproductive system, by their very nature, occur in a sexually dimorphic manner
and are influenced by exposure to reproductive hormones and dysregulated responses to sex steroids. The
contributions of estrogens to the pathobiology of most breast cancers and the positive impact of endocrine
therapies on outcome in this disease are well established. However, the incidence and long-term outcomes of
patients with a variety of non-reproductive cancers also demonstrate sexual dimorphism (e.g. lung cancer,
melanoma, glioblastoma and thyroid cancer). Whereas the mechanisms underlying these differences are
complex and multifactorial, established contributing factors are gender differences in smoking, sun exposure,
alcohol consumption, diet and occupational environments. Underappreciated are the contributions of sex
hormones themselves to the pathobiology of non-reproductive cancers. We have determined that cancer cell
extrinsic actions of estrogens/estrogen receptor-alpha (ERa) in the immune system and in the brain contribute
to tumor pathology in animal models of several different cancers. Estrogens facilitate the development of an
immune suppressive tumor microenvironment through direct actions on myeloid cells resulting in the attenuation
of T cell activation/function. Inhibition of ER action in specific loci in the brain, however, has the paradoxical effect
of increasing the growth of tumors from different tissues of origin. Understanding the cancer cell extrinsic
pharmacology of ER will inform how best to use existing endocrine therapies, be instructive as to approaches to
develop the next generation of modulators and enable the development of new drug combinations for the
treatment of breast and gynecological cancers and other cancers originating outside of the reproductive system.
Hypothesis: Maximal therapeutic efficacy of ER modulators for different cancers will be realized with the
development of interventions that achieve robust inhibition of cancer cell intrinsic actions of estrogens, exhibit
favorable effects on immune cell repertoire/function in tumors, and do not interfere with the homeostatic feedback
mechanisms in the brain that modulate the expression of processes that impact tumor biology.
Aims: (1) Define the mechanisms by which ER in tumor associated myeloid cells impacts tumor pathobiology.
(2) Define the mechanism(s) by which ER expression in the brain regulates processes which impact the growth
of tumors. (3) Evaluate therapeutic approaches to selectively target tumor cell extrinsic activities of ER.
Impact: The effectiveness of endocrine therapies for breast cancer and other estrogen-modulated cancers has
been limited by the focus on developing agents that target cancer cell intrinsic actions of ER/estrogens. By
defining the mechanisms by which ER regulates immune cell function, and how it regulates hypothalamic
activities that impact tumor biology in the periphery it will be possible to develop next gen...

## Key facts

- **NIH application ID:** 10781919
- **Project number:** 5R01CA276089-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Donald P McDonnell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $514,902
- **Award type:** 5
- **Project period:** 2023-02-07 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10781919

## Citation

> US National Institutes of Health, RePORTER application 10781919, Manipulating normal estrogen physiology as a therapeutic approach in cancer (5R01CA276089-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10781919. Licensed CC0.

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