TMIC-37. THE MICROENVIRONMENT OF A YOUNGER BRAIN IS MORE PERMISSIVE FOR BREAST CANCER BRAIN METASTASIS

摘要

Brain metastases are the most common tumors in the brain. Women diagnosed with breast cancer at a relatively young age have a higher risk of developing brain metastases and will often have a poorer outcome compared to women diagnosed at older age. We hypothesized that the brain microenvironment of young breast cancer patients promotes the formation of brain metastases. To test this hypothesis, we injected brain-seeking human triple negative MDA-MB-231BR breast cancer cells into the left-cardiac ventricle of young and old mice. We then compared metastatic tumor burden at study endpoint by quantifying the number of metastases in hematoxylin & eosin stained brain tissue sections. Consistent with our hypothesis, young mice developed two-fold (p<0.05) more brain metastases compared to older mice, and the metastases that developed were larger. Importantly, this effect of age was not model-specific, since young Balb/c mice injected with brain-seeking mouse triple negative 4T1-BR breast cancer cells also developed significantly (p<0.05) more brain metastases compared to older mice. Immunohistochemical analysis of the MDA-MB-231BR brain metastases revealed that there was similar level of Ki67 expression and GFAP-expressing reactive astrocytes between the two age cohorts. To further test whether this effect of age extends to other metastatic sites, we injected mouse (6DT1, HRM1, E0771, MVT1) and human (MDA-MB-231) breast cancer cells either orthotopically into the mammary fat pad or directly into the circulation of young and old mice. Age had no effect on metastatic burden in these models where the primary metastatic site is the lungs. Together, the data support our hypothesis that the age of the brain microenvironment can influence metastasis development, and suggest that the effect of age may depend on the metastatic site. Future work will aim to gain mechanistic insight into this phenomenon, with the goal that it may translate to age-specific therapies.