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

Nat Commun. 2016 Feb 4;7:10633. doi: 10.1038/ncomms10633.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / metabolism*
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Lobular / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Plasticity / drug effects
  • Cell Plasticity / physiology*
  • DNA-Binding Proteins
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Hyperplasia
  • Immunoblotting
  • Isoxazoles / pharmacology
  • Kaplan-Meier Estimate
  • MCF-7 Cells
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Resorcinols / pharmacology
  • Tumor Stem Cell Assay
  • Wnt Signaling Pathway*

Substances

  • 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
  • Antineoplastic Agents
  • Carrier Proteins
  • DNA-Binding Proteins
  • Isoxazoles
  • PAF protein, mouse
  • PCLAF protein, human
  • Resorcinols