The transcription factor FOXF1 promotes prostate cancer by stimulating the mitogen-activated protein kinase ERK5
Authors: Logan Fulford
Susan Kasper
Tien Le
David Milewski
Navin Ravishankar
Vladimir V Kalinichenko
Bruce Aronow
Vladimir Ustiyan
Sreeharsha Masineni
Yuqi Cai
Tanya V Kalin
Journal: Science signaling (2016)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: FOXF1; ERK5; prostate cancer; tumor growth; metastasis
Affiliations: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA., Department of Biomedical, Chemical, and Environmental Engineering, University of Cincinnati College of Engineering and Applied Science, Cincinnati, OH 45221, USA., Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. .

Abstract:  Forkhead box F1 (FOXF1) is a stromal transcription factor that is not expressed in epithelial cells of normal prostate tissue. The role of FOXF1 in cancer is conflicting; its loss in some cancers suggests a tumor suppressive function, but its abundance in others is associated with protumorigenic and metastatic traits. Extracellular signal-regulated kinase 5 (ERK5) is associated with advanced-stage prostate adenocarcinoma (PCa) in patients. We detected a population of FOXF1-positive tumor cells in aggressive mouse and human PCa. Using two murine orthotopic models of PCa, we found that overexpression of FOXF1 in Myc-CaP and TRAMP prostate tumor cells induced tumor growth in the prostate and progression to peritoneal metastasis. Increased growth of FOXF1-positive prostate tumors was associated with increased phosphorylation of ERK5, a member of the mitogen-activated protein kinase (MAPK) family. FOXF1 transcriptionally induced and directly bound to promoter regions of genes encoding the kinases MAP3K2 and WNK1, which promoted the phosphorylation and activation of ERK5. Knockdown of ERK5 or both MAP3K2 and WNK1 in FOXF1-overexpressing PCa cells reduced cell proliferation in culture and suppressed tumor growth and tumor metastasis when implanted into mice. In human tumors, FOXF1 expression correlated positively with that of MAP3K2 and WNK1 Thus, in contrast to some tumors where FOXF1 may function as a tumor suppressor, FOXF1 promotes prostate tumor growth and progression by activating ERK5 signaling. Our results also indicate that ERK5 may be a new therapeutic target in patients with FOXF1-positive PCa. 

Retracted: No

PubPeer comments:
 An Expression of Concern has been published: http: stke.sciencemag.org content 9 427 ra48 tab-pdf In the 10 May 2016 issue, Science Signaling published the Research Article  The transcription factor FOXF1 promotes prostate cancer by stimulating the mitogen-activated protein kinase ERK5 by L. Fulford, D. Milewski, V. Ustiyan, N. Ravishankar, Y. Cai, T. Le, S. Masineni, S. Kasper, B. Aronow, V. V. Kalinichenko, T. V. Kalin (1). The corresponding author and the research integrity officer of the corresponding authoru2019s institution notified Science Signaling that there was concern about image manipulation in Fig. 2C (images of caspase-3 staining) and fig. S4E (Western blots) and that an investigation is under way to determine if this represents research misconduct and to examine the data in other figures of the paper. Science Signaling is publishing this Editorial Expression of Concern to alert our readers while we await the outcome of the investigation. John F. Foley Editor Retraction Watch discussion: http: retractionwatch.com 2017 07 18 science-journal-flags-cancer-paper-investigation-image-manipulation , 
 Update: https: ori.hhs.gov content case-summary-fulford-logan ,