Journal
CELL SYSTEMS
Volume 6, Issue 3, Pages 329-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2018.02.001
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Funding
- NIH Common Fund Library of Network Cellular Signatures (LINCS) [HG008100]
- Susan G. Komen Foundation [SAC110012]
- National Cancer Institute of the NIH [F31CA200322]
- Knight Cancer Institute NCI [5P30CA069533-16]
- NIH [CA195469, P30EY010572, P30CA069533, S10OD012246]
- Prospect Creek Foundation
- Brigham Research Institute
- Knight Cancer Institute Multiscale Microscopy Core
- OHSU Center for Spatial Systems Biomedicine (OCSSB)
- MJ Murdock Charitable Trust
- NCI [CA16672]
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Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested similar to 2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-beta 1 (NRG1 beta), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells.
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