| Breast cancer subtype-specific interactions with the microenvironment dictate mechanisms of invasion. | |
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MedLine Citation:
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PMID: 21908556 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Most ductal breast carcinoma cells are weakly invasive in vitro and in vivo, suggesting that components of their microenvironment may facilitate a transition from in situ to invasive stages during progression. Here, we report that coculture of mammary fibroblasts specifically triggers invasive behavior in basal-type breast cancer cells through a ligand independent mechanism. When cultured alone in organotypic culture, both basal- and luminal-type breast cancer cells formed noninvasive spheroids with characteristics of ductal carcinoma in situ (DCIS). In contrast, when cocultured with mammary fibroblasts, basal-type spheroids exhibited invasive character whereas the luminal-type spheroids retained a benign and noninvasive duct-like architecture. Real-time imaging and functional studies revealed that the specificity of invasion was linked to a unique capacity of basal-type breast cancer cells to move within spheroids. Mammary fibroblasts induced invasion by triggering basal-type breast cancer cells to convert from a noninvasive program of mammary epithelial morphogenesis to an invasive program of sprouting endothelial angiogenesis. Contrary to the existing invasion models, soluble ligands produced by the fibroblasts were not sufficient to trigger invasion. Instead, basal-type invasion relied upon a Cdc42-dependent reorganization of collagen fibers in the extracellular matrix by fibroblasts. Inhibiting basal-type cell movement with clinically relevant drugs blocked invasion both in organotypic culture and in animals, suggesting a new treatment strategy for early-stage patients. Together our findings establish that fibroblast recruitment by basal-type breast cancer cells into early-stage tumors is sufficient to trigger their conversion from a benign, noninvasive DCIS-like stage to a malignant invasive stage. Furthermore, our findings suggest that different subtypes of breast cancer may require distinct types of contributions from the microenvironment to undergo malignant progression. |
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Authors:
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Tuyen T Dang; Amanda M Prechtl; Gray W Pearson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-09-09 |
Journal Detail:
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Title: Cancer research Volume: 71 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-01 Completed Date: 2012-01-09 Revised Date: 2013-02-19 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 6857-66 Citation Subset: IM |
Copyright Information:
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©2011 AACR. |
Affiliation:
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Harold C. Simmons Comprehensive Cancer Center and the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Breast / cytology Breast Neoplasms / classification, pathology* Carcinoma, Ductal, Breast / classification, pathology* Carcinoma, Intraductal, Noninfiltrating / pathology* Cell Movement / drug effects, physiology Cells, Cultured / cytology, physiology Coculture Techniques Collagen / physiology Culture Media, Conditioned / pharmacology Extracellular Matrix / physiology, ultrastructure Female Fibroblasts / cytology, physiology Humans Mice Mice, SCID Neoplasm Invasiveness / physiopathology*, prevention & control Neoplasm Transplantation Neovascularization, Pathologic / pathology Protein Kinase Inhibitors / pharmacology RNA, Small Interfering / pharmacology Spheroids, Cellular / physiology, transplantation Tumor Cells, Cultured / cytology, drug effects, physiology Tumor Microenvironment / physiology* cdc42 GTP-Binding Protein / antagonists & inhibitors, genetics, physiology |
| Grant Support | |
ID/Acronym/Agency:
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1R01CA155241/CA/NCI NIH HHS; 5T32CA124334-04/CA/NCI NIH HHS; R01 CA155241-01/CA/NCI NIH HHS; UL1-RR024982/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Culture Media, Conditioned; 0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; 9007-34-5/Collagen; EC 3.6.5.2/cdc42 GTP-Binding Protein |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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