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.
Highlights
Cancer stem cells (CSCs) contribute to tumour heterogeneity, therapy resistance and metastasis
We found that PCNA-associated factor (PAF) depletion or iCRT14 decreased the number of breast CSCs (Fig. 6c)
We previously found that PAF is highly expressed in colorectal and pancreatic cancer, and hyperactivates the Wnt/b-catenin and mitogen-activated protein kinase signalling pathways, which results in the initiation of tumorigenesis in mouse models[17,41]
Summary
Cancer stem cells (CSCs) contribute to tumour heterogeneity, therapy resistance and metastasis. PAF is highly expressed in breast cancer cells but not in mammary epithelial cells (MECs). PAF expression endows MECs with a self-renewing capacity and cell heterogeneity generation via Wnt signalling. 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. Accumulating evidence indicates that CSCs originate from SCs, progenitor cells or differentiated cells[14]. These models have not been experimentally tested. Our results revealed that PAF is highly expressed in breast cancer cells and plays key roles in inducing mammary epithelial cell (MEC) plasticity and maintaining breast cancer cell stemness
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