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Oncogene. 2019 Feb 22. doi: 10.1038/s41388-019-0756-z. [Epub ahead of print]

Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases.

Author information

1
Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
2
Department of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
3
Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
4
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
5
Women's Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
6
Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. Diana.Cittelly@ucdenver.edu.

Abstract

Breast cancer brain metastases (BM) affect younger women disproportionally, including those lacking estrogen receptor (ER), progesterone receptor, and HER2 (known as triple-negative breast cancer; TNBC). Previous studies in preclinical models showed that pre-menopausal levels of estradiol (E2) promote TNBC-BM through incompletely understood mechanisms involving reactive astrocytes. Herein, a novel mechanism involving E2-dependent upregulation of brain-derived neurotrophic factor (BDNF) in astrocytes, and subsequent activation of tumor cell tropomyosin kinase receptor B (TrkB), is identified. E2 increased experimental BM of TNBC 4T1BR5 and E0771 cells by 21 and 3.6 fold, respectively, compared to E2-depleted mice. ERα+ reactive astrocytes were found at early and late stages of BM, and E2 upregulated BDNF in ER+ reactive astrocytes in vitro and in vivo. TrkB was expressed in TNBC brain-trophic cell lines, BM-patient-derived xenografts, and breast cancer BM. Conditioned media from E2-treated astrocytes (CM-E2) activated TrkB and downstream AKT, ERK, and PLC-γ signaling in TNBC cells, increasing their invasiveness and tumor-initiating capability in vitro. The promotion of BM by E2-activated astrocytes was found to be more complex, involving feedback loops and other receptor tyrosine kinases. In 4T1BR5 cells, there was a positive feedback loop whereby astrocytic BDNF induced cancer cell BDNF translation. Upregulation of cancer cell BDNF was required to promote full invasiveness of 4T1BR5 in response to CM-E2, and was observed in brain metastatic cells in E2-treated mice in vivo. Moreover, the non-competitive BDNF/TrkB inhibitor ANA-12 reduced E2-induced 4T1BR5 BM to levels similar to OVX mice. BDNF also activated EGFR in TrkB+EGFR+ TNBC cells, suggesting that E2 action through astrocytes activates redundant pathways promoting BM. These findings have important therapeutic implications, as they provide a rationale to use E2-depletion therapies or TrkB inhibitors to prevent or delay development of BM in younger women.

PMID:
30796353
DOI:
10.1038/s41388-019-0756-z

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