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

Oncogene
Maria J Contreras-ZárateD M Cittelly

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, ...Continue Reading

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Citations

Sep 26, 2020·Cancers·Carmen IliPriscilla Brebi
Jun 17, 2020·Nature Communications·Erin N HoweSiyuan Zhang
Jul 10, 2020·Cancer Research·Manuel ValienteFrank Winkler
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Sep 22, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·R Alejandro Márquez-OrtizDiana M Cittelly

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Methods Mentioned

BETA
xenografts
ELISA

Software Mentioned

Elements
Aperio Digital Imaging
Aperio
Nis
ImageJ
Image Studio

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