# Elucidating The Role Of Androgen Receptor (AR) In Mediating Radioresistance In AR-Positive Breast Cancer

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $221,286

## Abstract

Elucidating the role of androgen receptor (AR) in mediating radioresistance in AR-positive breast cancer
How to make treatment more effective for the women with aggressive breast cancers for whom standard
therapies are ineffective; rationally designed treatment intensification
 Radiation therapy (RT) remains a mainstay of current clinical management of breast cancer but is least
effective in women with triple-negative breast cancer (TNBC). Additionally, TNBC is the most lethal form of
breast cancer, but the molecular drivers of this radioresistance are currently unknown. Given the fundamental
lack of knowledge regarding the mediators of radiation resistance and a furthered lack of targeted agents for
TNBC, it is clear that the development of additional targets for radiosensitization represents a critical unmet
clinical need. We previously identified that the androgen receptor (AR) plays an important role in mediating
radioresistance in AR-positive TNBC, though the exact mechanism of this radioresistance remains unclear.
Although antiandrogen therapy is effective in radiosensitizing AR+ TNBC, it is unclear whether antiandrogen
treatment in AR+ estrogen receptor-positive (ER+) breast cancer is similarly effective. As up to 70% of ER+
tumors also express AR, effective targeting of AR for radiosensitization has the potential to improve local control
in all AR+ breast cancer, not just AR+ TNBC.
 The goal of the proposed research is to develop more effective radiosensitizing treatment strategies for
woman with aggressive forms of breast cancer-including AR+ TNBC and AR+ Luminal B cancers that are ER+.
We hypothesize that AR mediates radioresistance in all AR+ breast cancer, and not just AR+ TNBC. We
further hypothesize that AR expression confers this radioresistance by controlling AR-mediated
transcription and activation of DNA repair genes after ionizing radiation and that this radioresistance
can be reversed by inhibition of AR-signaling using second generation anti-androgens. To test these
hypotheses, we will determine the degree of radiosensitization using enzalutamide with RT in AR+/ER+ patient
derived xenograft (PDX) cell lines and PDX models. We will also determine the gene transcription changes that
occur with anti-androgen treatment after radiation to determine how DNA binding of AR and AR-mediated
transcription changes after radiation treatment and inhibition of AR with antiandrogens with RT treatment.

## Key facts

- **NIH application ID:** 10746200
- **Project number:** 7R21CA267147-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Corey W. Speers
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $221,286
- **Award type:** 7
- **Project period:** 2022-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746200

## Citation

> US National Institutes of Health, RePORTER application 10746200, Elucidating The Role Of Androgen Receptor (AR) In Mediating Radioresistance In AR-Positive Breast Cancer (7R21CA267147-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10746200. Licensed CC0.

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