Abstract
Despite improvement of therapeutic treatments for breast cancer, the development of brain metastases has become a major limitation to life expectancy for many patients. Brain metastases show very commonly alterations in EGFR and HER2 driven pathways, of which PTEN is an important regulator. Here, we analyzed PTEN expression in 111 tissue samples of breast cancer brain metastases (BCBM). Loss of PTEN was found in a substantial proportion of BCBM samples (48.6%) and was significantly associated with triple-negative breast cancer (67.5%, p = 0.001) and a shorter survival time after surgical resection of brain metastases (p = 0.048). Overexpression of PTEN in brain-seeking MDA-MB-231 BR cells in vitro reduced activation of the AKT pathway, notably by suppression of Akt1 kinase activity. Furthermore, the migration of MDA-MB-231 BR cells in vitro was promoted by co-culturing with both astrocytes and microglial cells. Interestingly, when PTEN was overexpressed the migration was significantly inhibited. Moreover, in an ex vivo organotypic brain slice model, PTEN overexpression reduced invasion of tumor cells. This was accompanied by reduced astrocyte activation that was mediated by autocrine and paracrine activation of GM-CSF/ CSF2RA and AKT/ PTEN pathways. In conclusion, loss of PTEN is frequently detected in triple-negative BCBM patients and associated with poor prognosis. The findings of our functional studies suggest that PTEN loss promotes a feedback loop between tumor cells and glial cells, which might contribute to disease progression.
Highlights
The molecular basis of organ-specific metastasis patterns is currently under intensive investigation but remains unclear for most parts
When these samples were classified into molecular subtypes, 67.5% of all triple-negative brain metastases samples were negative for phosphatase and tensin homologue (PTEN), whereas only 29.3% of HER2 positive and 30.0% of hormone receptor positive samples were negative for PTEN expression (p = 0.01)
We describe the vital role of the tumor suppressor gene PTEN in the crosstalk between residential brain cells and tumor cells, which leads to rapid disease progression among patients with loss of PTEN
Summary
The molecular basis of organ-specific metastasis patterns is currently under intensive investigation but remains unclear for most parts. Brain www.impactjournals.com/oncotarget parenchyma offers particular conditions to metastasizing tumors cells due to both the blood-brain barrier and its extremely specialized microenvironment. The prognosis of cancer patients with brain metastases is often extremely poor and there is an urgent clinical need to deepen our understanding of factors leading to brain metastasis formation. There are different types of glial cells in the brain, of which mainly two have been associated with brain metastases, i.e. astrocytes and microglia [2]. Both astrocytes and microglia are non-proliferative in normal adult brain, but upon injury can be rapidly activated. In clinical samples it has been shown that both astrocytes and microglia may accumulate outside and inside the metastases with an impact on patient outcome [9]
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