Nuclear Janus-activated kinase 2/nuclear factor 1-C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing Forkhead box F1.
Progression to metastasis is the proximal cause of most cancer-related mortality. Yet much remains to be understood about what determines the spread of tumor cells. This paper describes a novel pathway in breast cancer that regulates epithelial-to-mesenchymal transition (EMT), motility, and invasiveness. We identify two transcription factors, nuclear factor 1-C2 (NF1-C2) and Forkhead box F1 (FoxF1), downstream of prolactin/nuclear Janus-activated kinase 2, with opposite effects on these processes. We show that NF1-C2 is lost during mammary tumor progression and is almost invariably absent from lymph node metastases. NF1-C2 levels in primary tumors correlate with better patient survival. Manipulation of NF1-C2 levels by expression of a stabilized version or using small interfering RNA showed that NF1-C2 counteracts EMT, motility, invasiveness, and tumor growth. FoxF1 was found to be a direct repressed target of NF1-C2. We provide the first evidence for a role of FoxF1 in cancer and in the regulation of EMT in cells of epithelial origin. Overexpression of FoxF1 was associated with a mesenchymal phenotype, increased invasiveness in vitro, and enhanced growth of breast carcinoma xenografts in nude mice. The relevance of these findings is strengthened by the correlation between FoxF1 expression and a mesenchymal phenoype in breast cancer cell isolates, consistent with the interpretation that FoxF1 promotes invasion and metastasis.
Department of Cell and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
Jeanette
J
Nilsson
Khalil
K
Helou
Anikó
A
Kovács
Pär-Ola
PO
Bendahl
Gunnar
G
Bjursell
Mårten
M
Fernö
Peter
P
Carlsson
Marie
M
Kannius-Janson
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051839:NFI Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic
C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D051839:NFI Transcription Factors; C497647:NFIC protein, human; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2