Blazquez, Raquel and Wlochowitz, Darius and Wolff, Alexander and Seitz, Stefanie and Wachter, Astrid and Perera-Bel, Julia and Bleckmann, Annalen and Beissbarth, Tim and Salinas, Gabriela and Riemenschneider, Markus J. and Proescholdt, Martin and Evert, Matthias and Utpatel, Kirsten and Siam, Laila and Schatlo, Bawarjan and Balkenhol, Marko and Stadelmann, Christine and Schildhaus, Hans-Ulrich and Korf, Ulrike and Reinz, Eileen and Wiemann, Stefan and Vollmer, Elena and Schulz, Mathias and Ritter, Uwe and Hanisch, Uwe K. and Pukrop, Tobias (2018) PI3K: A master regulator of brain metastasis-promoting macrophages/microglia. GLIA, 66 (11). pp. 2438-2455. ISSN 0894-1491, 1098-1136
Full text not available from this repository. (Request a copy)Abstract
Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis-promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan-PI3K Class I inhibitor with a good blood-brain-barrier penetrance, reduced their metastasis-promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BREAST-CANCER; CELLS; MACROPHAGE; BUPARLISIB; TISSUE; INTERFACE; RECEPTOR; PATHWAY; MICROENVIRONMENT; IDENTIFICATION; Astrocytes; BKM120; brain metastasis; macrophages; microglia; PI3K; RPPA |
| 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: | 10 Oct 2019 09:02 |
| Last Modified: | 10 Oct 2019 09:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13594 |
Actions (login required)
 |
View Item |
