Document Detail

HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment.
MedLine Citation:
PMID:  19701706     Owner:  NLM     Status:  MEDLINE    
Development of effective and durable breast cancer treatment strategies requires a mechanistic understanding of the influence of the microenvironment on response. Previous work has shown that cellular signaling pathways and cell morphology are dramatically influenced by three-dimensional (3D) cultures as opposed to traditional two-dimensional (2D) monolayers. Here, we compared 2D and 3D culture models to determine the impact of 3D architecture and extracellular matrix (ECM) on HER2 signaling and on the response of HER2-amplified breast cancer cell lines to the HER2-targeting agents Trastuzumab, Pertuzumab and Lapatinib. We show that the response of the HER2-amplified AU565, SKBR3 and HCC1569 cells to these anti-HER2 agents was highly dependent on whether the cells were cultured in 2D monolayer or 3D laminin-rich ECM gels. Inhibition of beta1 integrin, a major cell-ECM receptor subunit, significantly increased the sensitivity of the HER2-amplified breast cancer cell lines to the humanized monoclonal antibodies Trastuzumab and Pertuzumab when grown in a 3D environment. Finally, in the absence of inhibitors, 3D cultures had substantial impact on HER2 downstream signaling and induced a switch between PI3K-AKT- and RAS-MAPK-pathway activation in all cell lines studied, including cells lacking HER2 amplification and overexpression. Our data provide direct evidence that breast cancer cells are able to rapidly adapt to different environments and signaling cues by activating alternative pathways that regulate proliferation and cell survival, events that may play a significant role in the acquisition of resistance to targeted therapies.
Britta Weigelt; Alvin T Lo; Catherine C Park; Joe W Gray; Mina J Bissell
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-08-22
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  122     ISSN:  1573-7217     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-10     Completed Date:  2010-10-25     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  35-43     Citation Subset:  IM    
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MeSH Terms
Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal, Humanized
Antigens, CD29 / physiology
Antineoplastic Agents / pharmacology*
Cell Culture Techniques* / instrumentation
Cell Division / drug effects
Cell Line, Tumor / drug effects,  metabolism
Cell Survival / drug effects
Drug Delivery Systems
Drug Resistance, Neoplasm
Enzyme Activation / drug effects
Extracellular Matrix / physiology
Laminin / pharmacology
Neoplasm Proteins / physiology
Protein Kinase Inhibitors / pharmacology*
Quinazolines / pharmacology
Receptor, erbB-2 / antagonists & inhibitors,  physiology*
Signal Transduction / drug effects*,  genetics
Grant Support
P50CA58207/CA/NCI NIH HHS; R01 CA057621/CA/NCI NIH HHS; R01 CA057621-08/CA/NCI NIH HHS; R01 CA064786/CA/NCI NIH HHS; R01 CA064786-10/CA/NCI NIH HHS; R01 CA124891/CA/NCI NIH HHS; R01CA057621/CA/NCI NIH HHS; R01CA064786/CA/NCI NIH HHS; R01CA124891/CA/NCI NIH HHS; U54 CA112970/CA/NCI NIH HHS; U54 CA112970-01/CA/NCI NIH HHS; U54 CA126552/CA/NCI NIH HHS; U54 CA126552-04/CA/NCI NIH HHS; U54CA112970/CA/NCI NIH HHS; U54CA126552/CA/NCI NIH HHS
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antigens, CD29; 0/Antineoplastic Agents; 0/Gels; 0/Laminin; 0/Neoplasm Proteins; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0VUA21238F/lapatinib; 380610-27-5/pertuzumab; EC protein, human; EC, erbB-2; P188ANX8CK/trastuzumab

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