Active CREB1 Promotes a Malignant TGFb2 Autocrine Loop in Glioblastoma

In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identifi ed cAMP-responsive element–binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K–AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. SIGNIFICANCE: TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. Cancer Discov; 4(10); 1230–41. ©2014 AACR. See related commentary by Wotton, p. 1123. 1 Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain. 2 Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron University Hospital, Barcelona, Spain. 3 Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain. 4 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: Joan Seoane, Vall d’Hebron Institute of Oncology, Psg. Vall d’Hebron 119-129, 08035 Barcelona, Spain. Phone: 34-93-4894167; Fax: 34-93-489-4015; E-mail: [email protected] doi: 10.1158/2159-8290.CD-14-0275 ©2014 American Association for Cancer Research. on April 14, 2017. © 2014 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst August 1, 2014; DOI: 10.1158/2159-8290.CD-14-0275