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

Oncotarget. 2015 Aug 21;6(24):20697-710. doi: 10.18632/oncotarget.4136.

Jino Park ¹, Michaela Schlederer ² ³, Martin Schreiber ⁴, Ryan Ice ⁵ ⁶, Olaf Merkel ⁷, Martin Bilban ⁸, Sebastian Hofbauer ⁴, Soojin Kim ¹, Joseph Addison ⁵ ⁶, Jie Zou ⁹, Chunyan Ji ⁹, Silvia T Bunting ¹⁰, Zhengqi Wang ¹⁰, Menachem Shoham ¹¹, Gang Huang ¹², Zsuzsanna Bago-Horvath ³, Laura F Gibson ⁵, Yon Rojanasakul ⁵ ¹³, Scot Remick ⁵, Alexey Ivanov ⁵ ⁶, Elena Pugacheva ⁵ ⁶, Kevin D Bunting ¹⁰, Richard Moriggl ² ¹⁴, Lukas Kenner ² ³ ¹⁵, William Tse ¹

Affiliations

1 James Graham Brown Cancer Center, Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
2 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
3 Clinical Institute for Pathology, Medical University Vienna, Austria.
4 Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
5 Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA.
6 Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA.
7 National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.
8 Department of Laboratory Medicine, Medical University of Vienna and Core Facility Genomics, Core Facilities, Medical University of Vienna, Vienna, Austria.
9 Department of Hematology, Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, PR China.
10 Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA.
11 Case Western University School of Medicine, Cleveland, OH, USA.
12 Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
13 Department of Pharmaceutical Science, West Virginia University School of Medicine, Morgantown, WV, USA.
14 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria.
15 Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria.

PMID: 26079538 DOI: 10.18632/oncotarget.4136

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.

Keywords

AF1q; CD44; TCF7; Wnt; metastasis.

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