Brain metastases in Young Women
Young women with breast cancer have an increased risk of developing brain metastases independent of the primary tumor subtype. We have shown a novel role for the premenopausal hormone estradiol, in the promotion of brain metastasis in younger women.
Estradiol and ER- Breast Tumors
Our original manuscript in Oncogene, 2016 (PMID 26411365), described a novel pro-metastatic role for estradiol (E2) in the promotion of brain metastasis from ER- breast tumors. Using experimental metastasis models we provided the first pre-clinical evidence that pre-menopausal levels of E2 increases number, multiplicity and size of TNBC brain metastases in mice, and that ovariectomy in combination with aromatase inhibitors are effective in preventing brain metastatic colonization of brain-trophic 231BR cells. We demonstrated that ER+ astrocytes surround brain metastasis in humans and experimental metastasis models, and that E2-stimulated astrocytes upregulate several growth factors (EGF, TGFα, EREG), which then activate EGFR signaling in breast cancer cells.
Pre-menopausal levels of 17-b-estradiol promote brain colonization of ER- breast cancer cells
Pro-metastatic Effects of TrkB in the Brain
More recently, we described 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), as critical mediators of the pro-metastatic effects of E2 in the brain (PMID 30796353). We showed that E2 increased experimental BM of TNBC 4T1BR5 and E0771 cells through activation of TrkB on cancer cells. We showed that 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.
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 brain metastasis in younger women.
E2-depletion therapies or TrkB inhibitors may prevent or delay development of brain metastasis in younger women
Funded by R37 CA227984 & Metavivor Research Foundation
This project and Dr. Cittelly were highlighted in April 2019 in the National Minority Health Month Spotlight.