# G protein-coupled estrogen receptor GPER and breast carcinogenesis

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $158,942

## Abstract

Selective estrogen receptor (ER) modulators and downregulators (SERMs and SERDs, also
refereed to as anti-hormones) have saved the lives of millions of women with ER-positive breast
cancer. Unfortunately, approximately one-third of these women display intrinsic resistance to
these targeted therapies, while a similar fraction of women treated with anti-hormones will develop
resistance over time, resulting in recurrences of often more aggressive cancers. SERMs and
SERDs inhibit the classical nuclear estrogen receptor ERα, leading to the inhibition of cell
proliferation and survival. In contrast, our results have shown that these same drugs activate the
7-transmembrane spanning G protein-coupled estrogen receptor GPER, resulting in the
stimulation of the pro-survival PI3K/Akt axis. Furthermore, our recent studies have suggested that
this may occur through phosphorylation and inactivation of the FOXO3 pro-apoptotic transcription
factor. We have identified a collection of novel compounds that display strong selectivity for either
ERα or GPER. By combining these pharmacological approaches with genetic approaches, we
hypothesize that acquired resistance to anti-hormones involves their activation of GPER, resulting
in the inactivation of FOXO3. We propose to test this hypothesis with the following specific aims:
Aim 1 will test whether GPER mediates acquired breast cancer resistance to SERMs and SERDs.
Aim 2 will test whether the inactivation of FOXO3 represents a critical step in enhancing tumor cell
survival in the face of ERα inhibition. Aim 3 will employ a murine model of spontaneous breast
cancer to test whether blocking GPER activity in combination with tamoxifen treatment, or
alternatively selectively inhibiting ERα with novel drugs, prevents acquired resistance.
Significance: Completion of these aims will significantly advance our knowledge of the role of the
novel estrogen receptor GPER in acquired anti-hormone resistance in breast cancer. Identifying
GPER as a novel mediator in acquired anti-hormone resistance in breast cancer in combination
with the use novel highly selective ligands to be evaluated in this proposal could lead to significant
improvements in outcome for the150,000 women diagnosed with ER-positive breast cancer each
year.

## Key facts

- **NIH application ID:** 9997789
- **Project number:** 5R01CA163890-08
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Eric R Prossnitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $158,942
- **Award type:** 5
- **Project period:** 2012-08-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997789

## Citation

> US National Institutes of Health, RePORTER application 9997789, G protein-coupled estrogen receptor GPER and breast carcinogenesis (5R01CA163890-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997789. Licensed CC0.

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