NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
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Sabine Becker-Weimann1,*, Gaofeng Xiong2, Saori Furuta1, Ju Han1, Irene Kuhn1, Uri-David Akavia4, Dana Pe’er4, Mina J Bissell1, Ren Xu2,3,*
1 Life Sciences Division, Lawrence Berkeley National Laboratory1, Berkeley, CA
2 Markey Cancer Center, University of Kentucky, Lexington
3 Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington
4 Department of Biological Sciences, Columbia University, New York, NY
* Contributed equally to this work
Mina J Bissell, email:
Ren Xu, email:
Keywords: Disorganization gene signature, p65, RelB, three-dimensional tissue structure, tissue polarity.
Received: September 26, 2013 Accepted: October 12, 2013 Published: October 14, 2013
The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres (‘acini’), the malignant T4-2 cells that form large tumor-like clusters, and the ‘phenotypically reverted’ T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture.
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