AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis

• Type of Material: Article
• Authors: Jino Park, University of Louisville; Michaela Schlederer, Ludwig Boltzmann Institute for Cancer Research; Martin Schreiber, Medical University of Vienna; Ryan Ice, West Virginia University; Olaf Merkel, German Cancer Research Center; Martin Bilban, Medical University of Vienna; Sebastian Hofbauer, Medical University of Vienna; Soojin Kim, University of Louisville; Joseph Addison, West Virginia University; Jie Zou, Shandong University; Silvia Bunting, Emory University; Zhengqi Wang, Emory University; Menachem Shoham, Case Western University; Gang Huang, Cincinnati Children's Hospital Medical Center; Zsuzsanna Bago-Horvath, Medical University Vienna; Laura F. Gibson, West Virginia University; Yon Rojanasakul, West Virginia University; Scot Remick, West Virginia University; Alexey Ivanov, West Virginia University; Elena Pugacheva, West Virginia University; Kevin Bunting, Emory University; Richard Moriggl, Ludwig Boltzmann Institute for Cancer Research; Lukas Kenner, Ludwig Boltzmann Institute for Cancer Research; William Tse, University of Louisville
• Language: English
• Date: 2015-08-21
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Park et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.4136
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 6
• Issue: 24
• Start Page: 20697
• End Page: 20710
• Grant/Funding Information: RM was supported by SFB-F2807/SFB-F4707, from the Austrain ScienceFund (FWF).; This work was partly supported by the Career Development Award (CDA) from the American Society of Clinical Oncology, the John Hartford Foundation, and the T. Franklin William Scholar Program from the Association of Specialty Professors (WT).; Animal Models & Imaging Facility has been supported by the MBRCC and NIH grants P20 RR016440, P30 RR032138/GM103488 and S10RR026378.; This work was supported by grants from NIH/NCI (R01CA148671 to EP; 5P20RR016440 in part to AI) and the Susan G. Komen Foundation (KG110350 to AI; KG100539 to EP).; Flow Cytometry Facility was supported by MBRCC CoBRE, ARIA S10, Fortess S10 and WV InBRE grant GM103488/RR032138, RR020866, OD016165 and GM103434.; LK was supported by project P26011 from FWF and by Oncotyrol.
• Keywords: Life Sciences & Biomedicine; Science & Technology; Cell Biology; Wnt; FUNCTIONAL-ROLE; ONCOGENE AF1Q; Oncology; CD44; SUPPRESSOR GENE; WNT PATHWAY; ACUTE MYELOID-LEUKEMIA; AF1q; metastasis; INDUCED APOPTOSIS; PROTEIN-COUPLED RECEPTOR; GENE-EXPRESSION; TCF7; MESENCHYMAL TRANSITION; STEM-CELLS
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology; Biology, Cell

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 MDAdemonstrate 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.