title: In vitro reconstitution of breast cancer heterogeneity with multipotent cancer stem cells using small molecules.
abstract: A small fraction of tumor cells are thought to possess the potential for both multiple-lineage differentiation and self-renewal, which underlies the cancer stem cell hypothesis. However, the differentiation mechanisms of these cells have not been elucidated due to a lack of appropriate culture methods. Here, we established a culture condition for maintaining multipotent tumor cells from rat breast tumors using 4 small molecules. Cultured tumor cells in this condition retained their intrinsic myoepithelial features, expressing p63 and CK14 and vimentin. In a xenograft model, the p63-expressing cells formed epithelial tumors containing glandular, squamous and sebaceous compartments. Upon withdrawal of the small molecules, p63 and CK14 expression was lost, with concurrent increase in expression of mesenchymal markers. These transited cells acquired drug resistance and invasiveness and showed massive sarcomatoid tumorigenicity. Epithelial features could not be recovered by re-exposure to the small molecules in the transited cells. Here, we have identified multipotent cancer cells within primary mammary tumors and demonstrated that their plasticity is maintained by the small molecules.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamata
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Katsuda
authors.affiliation: Department of Reprogramming Science, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: tochiya@ncc.go.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D018929:Cell Culture Techniques; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male; D042361:Mammary Glands, Human / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D039902:Multipotent Stem Cells / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*
chemical_list: D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014746:Vimentin
keywords: Heterogeneity; Mammary tumor; Metaplasia; Multipotency; Small molecules