Hohensee, Ina and Chuang, Han-Ning and Grottke, Astrid and Werner, Stefan and Schulte, Alexander and Horn, Stefan and Lamszus, Katrin and Bartkowiak, Kai and Witzel, Isabell and Westphal, Manfred and Matschke, Jakob and Glatzel, Markus and Juecker, Manfred and Pukrop, Tobias and Pantel, Klaus and Wikman, Harriet (2017) PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression. ONCOTARGET, 8 (4). pp. 6155-6168. ISSN 1949-2553,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CANCER-CELLS; GENETIC ALTERATIONS; TUMOR-CELLS; MICROGLIA; SURVIVAL; LOOP; AKT; IDENTIFICATION; EXTRAVASATION; COLONIZATION; brain metastases; breast cancer; PTEN; microenvironment; astrocytes |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 27 Feb 2019 07:46 |
| URI: | https://pred.uni-regensburg.de/id/eprint/542 |
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