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PI3K: A master regulator of brain metastasis-promoting macrophages/microglia
- Source :
- Glia. 66(11)
- Publication Year :
- 2018
-
Abstract
- Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis-promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan-PI3K Class I inhibitor with a good blood-brain-barrier penetrance, reduced their metastasis-promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
- Subjects :
- 0301 basic medicine
Adult
Morpholines
Central nervous system
Buparlisib
Aminopyridines
Breast Neoplasms
Biology
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Mice
Phosphatidylinositol 3-Kinases
Breast cancer
Glial Fibrillary Acidic Protein
medicine
Animals
Humans
Enzyme Inhibitors
PI3K/AKT/mTOR pathway
Aged
Mice, Inbred BALB C
Microglia
Brain Neoplasms
Macrophages
TOR Serine-Threonine Kinases
Calcium-Binding Proteins
Microfilament Proteins
Reverse phase protein lysate microarray
Middle Aged
medicine.disease
3. Good health
Gene Expression Regulation, Neoplastic
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Neurology
chemistry
Cancer research
Biomarker (medicine)
Female
Brain metastasis
Signal Transduction
Subjects
Details
- ISSN :
- 10981136
- Volume :
- 66
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Glia
- Accession number :
- edsair.doi.dedup.....e71181b6e72cdbda7c43d5d33773732c