1. MTDH-SND1 Interaction Is Crucial for Expansion and Activity of Tumor-Initiating Cells in Diverse Oncogene- and Carcinogen-Induced Mammary Tumors
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Marina Chekmareva, Yongna Xing, Mario Andres Blanco, Liling Wan, Feng Guo, Rumela Chakrabarti, Min Yuan, Yong Wei, Yuling Hua, Hao Wu, Heath A. Smith, Minhong Shen, Xin Lu, Salina Yuan, Roderick T. Bronson, Bruce G. Haffty, and Yibin Kang
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Cancer Research ,SND1 ,Time Factors ,9,10-Dimethyl-1,2-benzanthracene ,Breast Neoplasms ,Mice, Transgenic ,Medroxyprogesterone Acetate ,Biology ,Transfection ,medicine.disease_cause ,Mice ,Mammary Glands, Animal ,Mammary tumor virus ,RNA interference ,Cell Line, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Gene silencing ,Genetic Predisposition to Disease ,Neoplasm Invasiveness ,Cell Proliferation ,Mice, Knockout ,Oncogene ,Membrane Proteins ,Nuclear Proteins ,RNA-Binding Proteins ,Cancer ,MTDH ,Cell Biology ,Cell Transformation, Viral ,Endonucleases ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Cell Transformation, Neoplastic ,HEK293 Cells ,Phenotype ,Mammary Tumor Virus, Mouse ,Oncology ,Neoplastic Stem Cells ,Cancer research ,Female ,RNA Interference ,Carcinogenesis ,Cell Adhesion Molecules ,Protein Binding - Abstract
SummaryThe Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis; however, its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. This functional significance of MTDH-SND1 interaction is further supported by clinical analysis of human breast cancer samples.
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