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.
Highlights
Brain metastases (BM) are a devastating complication of cancer in terms of cognitive, physical, and quality of life adverse outcomes
These cells express higher levels of epidermal growth factor receptor (EGFR) compared to other triplenegative breast cancers (TNBC) cell lines (4T1BR5, E0771, F2-7, Fig. 1a); we assessed whether E2-pellets alone (E2) could promote BM in the absence of EGFR overexpression
Ovariectomized (OVX) female mice were divided into three groups: implantation with slow release pellets containing (i) E2 (1 mg; maintains E2 levels equivalent to those found in pre-menopausal women; Supplementary Fig. 1a), (ii) placebo (OVX), or (iii) placebo mice treated with aromatase-inhibitor letrozole (OVX + Letrozole) to block peripheral E2-synthesis
Summary
Brain metastases (BM) are a devastating complication of cancer in terms of cognitive, physical, and quality of life adverse outcomes (rev in [1, 2]). Young pre-menopausal women with TNBC showed increased incidence of BM (53%) compared to postmenopausal women (28%) [12] These data suggested the novel hypothesis that pre-menopausal hormones such as estradiol (E2) may promote BM of TNBC by exerting effects on the brain microenvironment. BDNF cross-activated TrkB and EGFR in cancer cells expressing both receptors, suggesting a novel cooperative interaction between these signaling pathways in TNBC. These studies provide a novel mechanism whereby E2 action in the brain microenvironment activates oncogenic signals in TNBC promoting BM, and provide a rationale for clinical testing of E2-depletion therapies and TrkB inhibitors in preventing development of BM
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