Journal article
Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer
Molecular biology of the cell, Vol.22(14), pp.2423-2435
07/15/2011
DOI: 10.1091/mbc.E11-04-0306
PMCID: PMC3135469
PMID: 21613543
Abstract
Reduced epithelial cadherin (E-cad) is a hallmark of invasive carcinomas that have acquired epithelial-mesenchymal transition (EMT) phenotypes. Here we show that down-regulated E-cad expression induced by transforming growth factor-beta (TGF-beta) and EMT preceded breast cancer outgrowth in three-dimensional (3D) organotypic assays and in the lungs of mice. Pharmacological inhibitors against focal adhesion kinase prevented metastatic outgrowth of newly seeded organoids, but not that of their fully established counterparts. Interrogating the D2-HAN (hyperplastic alveolar nodule) model of breast cancer dormancy and metastasis showed that dormant D2.OR cells produced branched organoid morphologies in 3D-cultures, and expressed robust quantities of E-cad that was uncoupled from regulation by TGF-beta. In contrast, metastatic D2.A1 organoids were spherical and wholly lacked E-cad expression. Interestingly, D2.A1 cells engineered to re-express E-cad formed branched organoids, down-regulated beta 1 integrin expression, and failed to undergo metastatic outgrowth. The tumor-suppressing function of E-cad was inactivated by increased microenvironmental rigidity, and was not recapitulated by expression of an E-cad mutant lacking its extracellular domain. Twist expression, but not that of Snail, reinitiated metastatic outgrowth in dormant D2.OR cells. Our findings show that EMT and its down-regulated expression of E-cad circumvent breast cancer dormancy in part by facilitating beta 1 integrin expression necessary for metastatic outgrowth.
Details
- Title: Subtitle
- Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer
- Creators
- Michael K. Wendt - Case Western Reserve UniversityMolly A. Taylor - Case Western Reserve UniversityBarbara J. Schiemann - Case Western Reserve UniversityWilliam P. Schiemann - Case Western Reserve University
- Resource Type
- Journal article
- Publication Details
- Molecular biology of the cell, Vol.22(14), pp.2423-2435
- DOI
- 10.1091/mbc.E11-04-0306
- PMID
- 21613543
- PMCID
- PMC3135469
- NLM abbreviation
- Mol Biol Cell
- ISSN
- 1059-1524
- eISSN
- 1939-4586
- Publisher
- Amer Soc Cell Biology
- Number of pages
- 13
- Grant note
- CA129359 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA BC084561 / Department of Defense; United States Department of Defense R01CA129359 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) BCTR0706967 / Susan G. Komen for the Cure Foundation; Susan G. Komen Breast Cancer Foundation PF-09-120-01 / American Cancer Society
- Language
- English
- Date published
- 07/15/2011
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984460338002771
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