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Oncogene. 2018 Jul 11. doi: 10.1038/s41388-018-0349-2. [Epub ahead of print]

Nuclear respiratory factor 1 promotes spheroid survival and mesenchymal transition in mammary epithelial cells.

Author information

1
CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Jiangsu, 215123, China.
2
University of Chinese Academy of Sciences, Beijing, 100049, China.
3
Division of Hematology/Oncology, Department of Medicine, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA, 92093-0820, USA.
4
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.
5
CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Jiangsu, 215123, China. glsuo2013@sinano.ac.cn.

Abstract

Epithelial cells aggregate into spheroids when deprived of matrix, and the proclivity for spheroid formation and survival is a hallmark of normal and tumorigenic mammary stem cells. We show here that Nuclear Respiratory Factor 1 (NRF1) is a spheroid promoter by in silico identification of this transcription factor as highly connected to top shRNA-hits deduced from re-iterative selections for shRNAs enriched in MCF10A spheroids. NRF1-promoted spheroid survival is linked to its stimulation of mitochondrial OXPHOS, cell migration, invasion, and mesenchymal transition. Conversely, NRF1 knockdown in breast cancer MDA-MB-231 cells reduced spheroids, migration, invasion, and mesenchymal marker expression. NRF1 knockdown also reduced tumor burden in mammary fat pads and lungs of orthotopic- or tail vein-transplanted mice. With the Luminal A subtype of breast cancer, higher NRF1 expression is associated with lower survival. These results show that NRF1, an activator of mitochondrial metabolism, supports mammary spheroid survival and tumor development.

PMID:
29995872
DOI:
10.1038/s41388-018-0349-2

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