title: Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.
abstract: Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial-mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re-undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple-negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus-labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E-box-binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT-MET dynamics that could affect the development of triple-negative breast cancer.
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Sakane
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tominaga
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.affiliation: Department of Breast and Endocrine Surgery, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Department of Breast and Endocrine Surgery, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: Department of Breast and Endocrine Surgery, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Tada
authors.affiliation: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Goshima
authors.affiliation: Department of Life Science and Medical Bio-Science, Waseda University, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Semba
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun-Ichiro
authors.identifier: http://orcid.org/0000-0001-6389-7036
authors.initials: JI
authors.lastname: Inoue
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: 
  EMT
  ; 
  MET
  ; Breast cancer; EMT-inducing transcription factor; cancer development