Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.
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.
['Yamamoto|Mizuki|M|', 'Sakane|Kota|K|', 'Tominaga|Kana|K|', 'Gotoh|Noriko|N|', 'Niwa|Takayoshi|T|', 'Kikuchi|Yasuko|Y|', 'Tada|Keiichiro|K|', 'Goshima|Naoki|N|', 'Semba|Kentaro|K|', 'Inoue|Jun-Ichiro|JI|http://orcid.org/0000-0001-6389-7036']
D045744:Cell Line, Tumor D049109:Cell Proliferation D058750:Epithelial-Mesenchymal Transition D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D059630:Mesenchymal Stem Cells D064726:Triple Negative Breast Neoplasms D000071799:Zinc Finger E-box-Binding Homeobox 1
Breast cancer EMT MET EMT-inducing transcription factor cancer development