Journal
NATURE CELL BIOLOGY
Volume 16, Issue 4, Pages 345-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2930
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Funding
- American Cancer Society [120668-RSG-11-047-01-DMC]
- National Institutes of Health Director's New Innovator Award Program [1-DP2-OD006464]
- ew Scholars Program in the Biomedical Sciences
- David and Lucile Packard Foundation
- Breast Cancer Research Program Postdoctoral Fellowship Award from the Department of Defense [W81XWH-11-1-0037]
- National Science Foundation
- University of Virginia
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Basal-like breast carcinoma is characterized by poor prognosis and high intratumour heterogeneity. In an immortalized basal-like breast epithelial cell line, we identified two anticorrelated gene-expression programs that arise among single extracellular matrix (ECM)-attached cells during organotypic three-dimensional culture. The first contains multiple TGF-beta-related genes including TGFBR3, whereas the second contains JUND and the basal-like marker KRT5. TGFBR3 and JUND interconnect through four negative-feedback loops to form a circuit that exhibits spontaneous damped oscillations in three-dimensional culture. The TGFBR3-JUND circuit is conserved in some premalignant lesions that heterogeneously express KRT5. The circuit depends on ECM engagement, as detachment causes a rewiring that is triggered by RPS6 dephosphorylation and maintained by juxtacrine tenascin C, which is critical for intraductal colonization of basal-like breast cancer cells in vivo. Intratumour heterogeneity need not stem from partial differentiation and could instead reflect dynamic toggling of cells between expression states that are not cell autonomous.
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