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Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.008
vdae090.008
Final Category: Basic Science Brain Metastases
AcademicSubjects/MED00300
AcademicSubjects/MED00310
BSBM-10 GENETIC DELETION OF ERΑ OR ERΒ IN REACTIVE ASTROCYTES DECREASES REACTIVE GLIOSIS AND PROMOTES BRAIN METASTASIS
Koliavas Stella University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Contreras-Zárate Maria J University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Jaramillo-Gomez Jenny A University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Fox Morgan University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Nguyen Alicia University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Cittelly Diana M University of Colorado Anschutz Medical Campus, Aurora, CO, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i3i3
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Astrocytes surround brain metastasis (BM) and play both anti-metastatic and pro-metastatic roles throughout BM progression. We have shown that pre-menopausal levels of 17-β-Estradiol (E2) promotes BM of estrogen receptor (ER) negative breast cancer (BC), in part by stimulating ER+ astrocytes to secrete factors that promote proliferation, migration, and invasion of ER-BC cells. E2 exert its function through activation of ERα or ERb, and astrocytic ERα and ERβ play diverse and often interdependent roles modulating neuroinflammatory responses in the brain. Yet, how ERs impact astrocytic function in the context of BM remains unknown. We hypothesize that genetic deletion of astrocytic ERs modulates their function during BM progression and blocks E2-dependent BM. Using a Cre-loxP system, we selectively deleted ERα or ERβ in GFAP+ reactive astrocytes (GFAPCre/+), and measured BM progression after intracardiac injection of E0771 GFPLuc+ cells in ovariectomized (OVX) female mice treated or not with E2. While E2 increased BM in control GFAP+/+ERαfl/fl and GFAP+/+ERbfl/fl mice compared to OVX mice, OVX mice with ERα or ERβ deletion in reactive astrocytes (GFAPCre/+ERαfl/fl or GFAPCre/+ERbfl/fl) showed increased BM with levels comparable to those of E2-treated control mice. Thus, genetic deletion of ERs in GFAP+ reactive astrocytes promoted E2-independent growth of BM. Immunofluorescence staining showed that BM- associated stroma of mice with ERα and ERb deletion contained significantly less reactive astrocytes (GFAP+) than control mice, suggesting that loss of ERs decreases reactive gliosis. Brain immune profiling of BM- bearing mice showed loss of ERα or ERb had a significantly increased fraction of pro-inflammatory microglia compared to OVX-control mice, suggesting that loss of astrocytic ERα and ERb promotes a neuroinflammatory TME. Together, these data suggest that loss of astrocytic ERs promotes E2-independent BM by suppressing the ability of astrocytes to become reactive and exert their anti-metastatic role through BM progression.
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