title: AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis.
abstract: AF1q is an MLL fusion partner that was identified from acute myeloid leukemia (AML) patients with t (1; 11) (q21; q23) chromosomal abnormality. The function of AF1q is not yet fully known, however, elevated AF1q expression is associated with poor clinical outcomes in various malignancies. Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance. In xenograft models, enforced AF1q expression in breast cancer cells also promotes liver metastasis and lung colonization. In a cohort of 63 breast cancer patients, higher percentages of AF1q-positive cancer cells in primary sites were associated with significantly poorer overall survival (OS), disease-free survival (DFS), and brain metastasis-free survival (b-MFS). Using paired primary/metastatic samples from the same patients, we demonstrate that AF1q-positive breast cancer cells become dynamically dominant in the metastatic sites compared to the primary sites. Our findings indicate that breast cancer cells with a hyperactive AF1q/TCF7/CD44 regulatory axis in the primary sites may represent "metastatic founder cells" which have invasive properties.
authors.affiliation: James Graham Brown Cancer Center, Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Jino
authors.initials: J
authors.lastname: Park
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute for Pathology, Medical University Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Schreiber
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.|Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Ice
authors.affiliation: National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna and Core Facility Genomics, Core Facilities, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.affiliation: Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hofbauer
authors.affiliation: James Graham Brown Cancer Center, Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Soojin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.|Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Addison
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ji
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Silvia T
authors.initials: ST
authors.lastname: Bunting
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Zhengqi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Case Western University School of Medicine, Cleveland, OH, USA.
authors.forename: Menachem
authors.initials: M
authors.lastname: Shoham
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Clinical Institute for Pathology, Medical University Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bago-Horvath
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.|Department of Pharmaceutical Science, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.
authors.forename: Scot
authors.initials: S
authors.lastname: Remick
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.|Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.|Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Pugacheva
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute for Pathology, Medical University Vienna, Austria.|Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: James Graham Brown Cancer Center, Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: William
authors.initials: W
authors.lastname: Tse
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D060449:Wnt Signaling Pathway
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C091736:MLLT11 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human
keywords: AF1q; CD44; TCF7; Wnt; metastasis