title: PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness.
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.
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Xin
authors: X
authors: Wang
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Youn-Sang
authors: YS
authors: Jung
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Sohee
authors: S
authors: Jun
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Sunhye
authors: S
authors: Lee
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Wenqi
authors: W
authors: Wang
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Andrea
authors: A
authors: Schneider
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Young
authors: Y
authors: Sun Oh
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Steven H
authors: SH
authors: Lin
authors: Department of Molecular Biology, Pusan National University, Busan 609-735, Korea.
authors: Bum-Joon
authors: BJ
authors: Park
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Junjie
authors: J
authors: Chen
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.
authors: Khandan
authors: K
authors: Keyomarsi
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Z6.6034, Unit 1052, Houston, Texas 77030, USA.|Program in Genes and Development, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jae-Il
authors: JI
authors: Park
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism*; D018275:Carcinoma, Lobular / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000066670:Cell Plasticity / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia; D015151:Immunoblotting; D007555:Isoxazoles / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D060449:Wnt Signaling Pathway
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007555:Isoxazoles; C561966:PAF protein, mouse; C425208:PCLAF protein, human; D012118:Resorcinols