Oncotarget

Research Papers:

PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression

Ina Hohensee, Han-Ning Chuang, Astrid Grottke, Stefan Werner, Alexander Schulte, Stefan Horn, Katrin Lamszus, Kai Bartkowiak, Isabell Witzel, Manfred Westphal, Jakob Matschke, Markus Glatzel, Manfred Jücker, Tobias Pukrop, Klaus Pantel and Harriet Wikman _

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Oncotarget. 2017; 8:6155-6168. https://doi.org/10.18632/oncotarget.14047

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Abstract

Ina Hohensee1, Han-Ning Chuang2,*, Astrid Grottke3,*, Stefan Werner1, Alexander Schulte4, Stefan Horn5, Katrin Lamszus4, Kai Bartkowiak1, Isabell Witzel6, Manfred Westphal4, Jakob Matschke7, Markus Glatzel7, Manfred Jücker3, Tobias Pukrop2,8, Klaus Pantel1, Harriet Wikman1

1Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

2Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany

3Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

4Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

5Bone Marrow Transplantation Unit, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

6Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

7Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, 20246 Hamburg, Germany

8Department of Medicine III, University Medical Center Regensburg, 93053 Regensburg, Germany

*Shared senior author

Correspondence to:

Harriet Wikman, email: h.wikman@uke.de

Keywords: brain metastases, breast cancer, PTEN, microenvironment, astrocytes

Received: August 04, 2016     Accepted: December 13, 2016     Published: December 20, 2016

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.


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