# MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $362,569

## Abstract

Estrogen receptor (ER)-positive breast tumors are treated with endocrine therapies which specifically target the
ER. Patients can remain disease-free for many years; however, resistance to treatment eventually develops,
and the majority of women will suffer a recurrence of metastatic cancer. We hypothesized that the key to the
long-term treatment of women with ER-positive breast cancers was to focus on identifying novel mechanisms
of resistance using metastatic tumors resistant to therapy where tumor evolution and clonal selection have
occurred. We identified the androgen receptor (AR) as a new clinical target which was up regulated in
resistant, metastatic tumors. We have learned that AR functionally collaborates with ER, and that resistance
may be associated with a failure of hormone therapy to completely block both androgen and estrogen
signaling. We have also discovered that AR-overexpressing cells become metastatic in vivo. Furthermore, we
were the first to identify that the estrogen receptor ESR1 gene can be mutated in metastatic tumors; acquiring
hormone-independent and endocrine therapy-resistant functions which we hypothesize will also be impacted
by ligand-independent AR signaling. Importantly, cells with ESR1 mutations also up-regulate AR,
demonstrating a unique relationship between these mutations and AR. Our Aims are: (1) To determine if
receptor crosstalk (WT or mutant ER with AR) is a mechanism of resistance to hormonal agents, (2) To
determine whether AR employs novel nuclear receptor interactions to drive hormone resistance, and (3) To
determine AR and ESR1 mutant effects on invasion and metastasis. Key success has been made in
developing resistant models with endogenous up regulation of AR coincident with acquired resistance, and we
have already identified potential AR-mediated candidate resistance mechanisms. Undoubtedly hormone
therapy resistance in patients is multifactorial and will require combination hormonal and targeted therapy
along with knowledge of the activation status of key pathways, such as those arising from mutations in ER in
metastatic tumors. Our work will impact a large number of women with ER-positive breast cancer who recur
with therapy-resistant disease.

## Key facts

- **NIH application ID:** 9884532
- **Project number:** 5R01CA207270-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Suzanne AW Fuqua
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,569
- **Award type:** 5
- **Project period:** 2017-03-07 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884532

## Citation

> US National Institutes of Health, RePORTER application 9884532, MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER (5R01CA207270-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9884532. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*