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

Jino Park, Michaela Schlederer, Martin Schreiber, Ryan Ice, Olaf Merkel, Martin Bilban, Sebastian Hofbauer, Soojin Kim, Joseph Addison, Jie Zou, Chunyan Ji, Silvia T. Bunting, Zhengqi Wang, Menachem Shoham, Gang Huang, Zsuzsanna Bago-Horvath, Laura F. Gibson, Yon Rojanasakul, Scot Remick, Alexey IvanovElena Pugacheva, Kevin D. Bunting, Richard Moriggl, Lukas Kenner, William Tse

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20697-20710
Number of pages14
JournalOncotarget
Volume6
Issue number24
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • AF1q
  • CD44
  • Metastasis
  • TCF7
  • Wnt

ASJC Scopus subject areas

  • Oncology

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