PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness.

Xin Wang, Youn-Sang Jung, Sohee Jun, Sunhye Lee, Wenqi Wang, Andrea Schneider, Young Sun Oh, Steven H Lin, Bum-Joon Park, Junjie Chen, Khandan Keyomarsi, Jae-Il Park

Index: Nat. Commun. 7 , 10633, (2016)

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Abstract

Cancer stem cells (CSCs) contribute to tumour heterogeneity, therapy resistance and metastasis. However, the regulatory mechanisms of cancer cell stemness remain elusive. Here we identify PCNA-associated factor (PAF) as a key molecule that controls cancer cell stemness. PAF is highly expressed in breast cancer cells but not in mammary epithelial cells (MECs). In MECs, ectopic expression of PAF induces anchorage-independent cell growth and breast CSC marker expression. In mouse models, conditional PAF expression induces mammary ductal hyperplasia. Moreover, PAF expression endows MECs with a self-renewing capacity and cell heterogeneity generation via Wnt signalling. Conversely, ablation of endogenous PAF induces the loss of breast cancer cell stemness. Further cancer drug repurposing approaches reveal that NVP-AUY922 downregulates PAF and decreases breast cancer cell stemness. Our results unveil an unsuspected role of the PAF-Wnt signalling axis in modulating cell plasticity, which is required for the maintenance of breast cancer cell stemness.