Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis

Shaheen S. Sikandar, Angera H. Kuo, Tomer Kalisky, Shang Cai, Maider Zabala, Robert W. Hsieh, Neethan A. Lobo, Ferenc A. Scheeren, Sopheak Sim, Dalong Qian, Frederick M. Dirbas, George Somlo, Stephen R. Quake, Michael F. Clarke

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Previous studies have proposed that epithelial to mesenchymal transition (EMT) in breast cancer cells regulates metastasis, stem cell properties and chemo-resistance; most studies were based on in vitro culture of cell lines and mouse transgenic cancer models. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Using in vivo lineage tracing and triple negative breast cancer (TNBC) patient derived xenografts we demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in TNBC is independent of expression of EMT-associated genes. In breast cancer, while a subset of cells with epithelial and mesenchymal phenotypes have stem cell activity, in many cells that have lost epithelial characteristics with increased expression of mesenchymal genes, have decreased tumor-initiating capacity and plasticity. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells.

Original languageEnglish
Article number1669
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - 21 Nov 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s).

Funding

This work was supported by NIH/NCI grant 5P01 CA139490-05, NIH/NCI grant 5U01 CA154209-04, NIH/NCI 5R01 CA100225-09, Department of Defense grant W81XWH-11-1-0287, Department of Defense/Breast Cancer Research Program (BCRP) Innovator Award W81XWH-13-1-0281, DoD Post-doctoral Fellowship W81XWH-12-1-0020 to S.S. We thank Patty Lovelace for her assistance with flow cytometry and Stanford Neuroscience Microscopy Service, supported by NIH NS069375. BD FACSAriaII was purchased by NIH S10 shared instrumentation grant 1S10RR02933801.

FundersFunder number
Department of Defense/BreastW81XWH-13-1-0281
NIH/NCI5R01 CA100225-09, 5U01 CA154209-04, 5P01 CA139490-05
National Institutes of Health1S10RR02933801, NS069375
U.S. Department of DefenseW81XWH-11-1-0287, W81XWH-12-1-0020

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