title: Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer.
abstract: The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development. Growth and survival of preneoplastic as well as neoplastic mammary epithelial cells is dependent on the formation of a Snail1/HDAC1/p53 tri-molecular complex that deacetylates active p53, thereby promoting its proteasomal degradation. Our findings identify Snail1 as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wild-type p53 in breast cancer.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Ni
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Teng
authors.initials: T
authors.lastname: An
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Wen-Cong
authors.initials: WC
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Xu
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: R
authors.initials: R
authors.lastname: Grant Rowe
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Yong-Shun
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Scherer
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Feinberg
authors.affiliation: Department of Mathematics, Shanghai Normal University, Shanghai 200234, China.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Zheng
authors.affiliation: Department of Hematology and Oncology, The Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China.
authors.forename: Bao-An
authors.initials: BA
authors.lastname: Chen
authors.affiliation: Department of Biostatistics and Computational Biology, The Dana-Farber Cancer Institute, Harvard School of Public Health, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhao-Qiu
authors.initials: ZQ
authors.lastname: Wu
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1