Characteristic overexpression of the forkhead box transcription factor Foxf1 in Patched-associated tumors.
Patients with nevoid basal cell carcinoma syndrome carry germline mutations in the tumor suppressor gene Patched 1 (PTCH1) and are predisposed to develop basal cell carcinoma (BCC), medulloblastoma (MB), and rhabdomyosarcoma (RMS). These tumors are also present in the murine model for Ptch1 deficiency, the Ptch1neo67/+ mouse. Previous studies, including those from our laboratory, have shown that the forkhead box transcription factor Foxf1 is highly expressed in RMS of human and murine origin. We report on a more common role of Foxf1 in Ptch1-associated tumorigenesis, since we found a striking up-regulation of Foxf1 expression in Ptch1-associated BCC and MB compared with the respective non-neoplastic tissue. This overexpression was accompanied by increased levels of the Hedgehog target gene Gli1 as well as the putative Foxf1 targets Bmi1 and Notch2 in these tumors. We also describe a striking Foxf1 activation in Ptch1 null embryos. In contrast, basal expression levels of Foxf1, Gli1, Bmi1 and Notch2 were detected in a variety of adult mouse tissues, such as liver, kidney, spleen, lung, heart and brain. In conclusion, our study suggests that Foxf1 expression is characteristically up-regulated in tumors with a constitutively activated Hedgehog signaling pathway thereby defining a key role for Foxf1 in Hedgehog-associated tumorigenesis.
Wendling
Danielle S
DS
Department of Pediatric Surgery, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany.
Lück
Clemens
C
von Schweinitz
Dietrich
D
Kappler
Roland
R
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
D000199:Actins; C489421:Bmi1 protein, mouse; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C497765:Notch2 protein, mouse; D009687:Nuclear Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011518:Proto-Oncogene Proteins; C000606240:Ptch1 protein, mouse; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D000071676:Zinc Finger Protein GLI1; D063150:Polycomb Repressive Complex 1