Brain Metastases and Estrogen: Is There a Link in Triple-Negative Breast Cancer?
Posted: Friday, April 26, 2019
Estradiol may drive the upregulation of brain-derived neurotrophic factor (BDNF) in astrocytes and the subsequent activation of tumor cell tropomyosin kinase receptor B (TrkB), leading to brain metastasis in patients with triple-negative breast cancer. Diana M. Cittelly, PhD, of the University of Colorado School of Medicine, and colleagues proposed in Oncogene that estrogen can affect brain cells in ways to promote cell migration and invasiveness.
“The [breast] cancer cells aren’t responsive to estrogen, but estrogen influences the microenvironment. We found that astrocytes…are estrogen-responsive. When they are stimulated with estrogen, they produce chemokines, growth factors, and other things that promote brain metastasis,” said Dr. Cittelly in an institutional press release.
Using a combination of patient samples, cell lines, and animal studies, researchers demonstrated the effects of estradiol on brain metastases. In animal studies, estradiol increased the amount of brain metastases 3.6- to 21-fold compared with estradiol-depleted mice. Estrogen receptor–positive astrocytes could be found at both early and late stages of metastasis, and estradiol was found to upregulate BDNF in these astrocytes both in vivo and in vitro.
In addition, TrkB was seen in triple-negative breast cancer brain-trophic cell lines, brain metastasis patient xenografts, and breast cancer brain metastasis. Estradiol was found to activate TrkB, which leads to downstream upregulation of ERK, AKT, and PLC-gamma signaling in cancer cells. Brain metastasis by estradiol-activated astrocytes involves a more complex signaling pattern involving feedback loops and receptor tyrosine kinases. A BDNF/TrkB inhibitor was able to reduce estradiol-induced brain metastases in one cell line.
Disclosure: The study authors reported no conflicts of interest.
