title: PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression.
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.
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Hohensee
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Han-Ning
authors.initials: HN
authors.lastname: Chuang
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Grottke
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Werner
authors.affiliation: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulte
authors.affiliation: Bone Marrow Transplantation Unit, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Horn
authors.affiliation: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Bartkowiak
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Witzel
authors.affiliation: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Matschke
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jücker
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.|Department of Medicine III, University Medical Center Regensburg, 93053 Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary* / Q000601:surgery; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D018450:Disease Progression; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009457:Neuroglia / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000601:surgery
chemical_list: C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PTEN; astrocytes; brain metastases; breast cancer; microenvironment