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

doi:10.1038/ncomms10633

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.

Authors

Xin Wang¹, Youn-Sang Jung¹, Sohee Jun¹, Sunhye Lee¹, Wenqi Wang¹, Andrea Schneider¹, Young Sun Oh¹, Steven H Lin¹, Bum-Joon Park², Junjie Chen¹, Khandan Keyomarsi¹, Jae-Il Park^{1

3

4}

Affiliations

¹ Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
² Department of Molecular Biology, Pusan National University, Busan 609-735, Korea.
³ Program in Genes and Development, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
⁴ Graduate School of Biomedical Sciences, University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding