Pten Is An Important Mediator Of Tumor And Glia Cell Crosstalk In Breast Cancer Brain Metastasis

With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Loss of Phosphatase and tensin homolog (PTEN) is correlated with occurrence of breast cancer brain metastases, but its functional role in metastases formation remains unclear. Here, we first assessed the clinical role of PTEN expression in brain metastases, by performing immunohistochemical analyses on a TMA consisting of 132 breast cancer brain metastases samples. Loss of PTEN protein expression was found in 48.6% of brain metastases, and significantly associated with the triple-negative breast cancer subtype (67.5%, p = 0.01). Loss of PTEN was furthermore significantly associated with shorter overall survival (p = 0.048). We then investigated the biological role of PTEN in breast cancer brain metastasis formation by overexpressing PTEN in the triple-negative brain metastatic breast cancer cell cline MDA-MB-231 BR. Overexpression of PTEN was shown to reduce the AKT pathway activation especially by reducing the Akt1 kinase activity. Coculture experiments with glia cells (astrocytes and microglia) showed that astrocytes can inhibit cell proliferation of the tumor cells in a PTEN dependent manner. Both astrocytes and microglia promote migration of MDA-MB-231 BR cells in a PTEN-dependent manner in vitro. Using an organotypic brain slice model as a representation of the brain tumor microenvironment, the PTEN-dependent invasion of tumor cells could be confirmed. Furthermore, PTEN overexpression reduced the astrocyte activation. Coculture experiments with glia cells showed PTEN-dependent, differential cytokine expression. We could identify an endocrine and paracrine regulation between tumor cells and astrocytes, where GM-CSF, CSF2RA, EGF and PTEN play an important role. In conclusion, loss of PTEN is associated with poor prognosis and is an important mediator of a “vicious circle” mediated by the cross talk between tumor cells and glia cells. Citation Format: Harriet Wikman, Ina Hohensee, Han-Ning Chuang, Astrid Grottke, Stefan Werner, Alexander Schulte, Jakob Matschke, Markus Glatzel, Stefan Horn, Manfred Jucker, Tobias Pukrop, Klaus Pantel. PTEN is an important mediator of tumor and glia cell crosstalk in breast cancer brain metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1571.