Stein, T., Cosimo, E., Yu, X., Smith, P. R., Simon, R., Cottrel, L., Pringle, M., Bell, A. K., Lattanzio, L., Sauter, G., Lo Nigro, C., Crook, T., Machesky, L. M., Gusterson, B. A. (2010) Loss of Reelin Expression in Breast Cancer Is Epigenetically Controlled and Associated with Poor Prognosis. AMERICAN JOURNAL OF PATHOLOGY, 177 (5). pp. 2323-2333. ISSN 0002-9440

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Abstract

Reelin is a secreted, signaling protein associated with neuronal cell positioning and migration. Recently, reelin was found to be epigenetically silenced in gastric and pancreatic cancers in which down-regulation was associated with increased migratory ability and reduced survival. Here we analyzed reelin expression by immunohistochemistry in 17 normal breast tissue samples from reduction mammoplasties and in two independent tissue microarrays of 136 and more than 2000 breast cancer biopsy samples, respectively. Results were analyzed with regard to clinical parameters, including BRE (Bloom, Richardson, Elston) grade, nodal status, estrogen receptor and HER2 status, and overall survival. Reelin was expressed in the luminal epithelium and myoepithelium of the normal human breast but not in cancerous breasts. Loss of reelin protein expression correlated significantly with decreased survival (P = 0.01) and positive lymph node status (P < 0.001). By measuring reelin expression and promoter methylation status in 39 primary breast tumors, as well as in breast cancer-derived cell lines before and after decitabine treatment, we established that reelin expression levels correlated inversely with promoter methylation status, whereas demethylation increased reelin mRNA expression in vitro. Reelin overexpression in MDA-MB231 cells, as well as incubation with recombinant reelin, suppressed cell migration, invadopodia formation, and invasiveness in vitro. We conclude that reelin may play an important role in controlling invasiveness and metastatic potential of breast cancer cells and that its expression is controlled by promoter methylation. (Am J Pathol 2010 177:2323-2333; DOI: 10.2353/ajpath.2010.100209)

Item Type:	Article
All Authors:	Stein, T., Cosimo, E., Yu, X., Smith, P. R., Simon, R., Cottrel, L., Pringle, M., Bell, A. K., Lattanzio, L., Sauter, G., Lo Nigro, C., Crook, T., Machesky, L. M., Gusterson, B. A.
Uncontrolled Keywords:	APOE RECEPTOR 2; NEURONAL MIGRATION; BRAIN-DEVELOPMENT; TYROSINE PHOSPHORYLATION; ALPHA-3-BETA-1 INTEGRIN; VLDL RECEPTOR; DISABLED-1; MOUSE; GENE; PROTEIN
Funding Acknowledgement:	Breakthrough Breast Cancer ; International Breast Cancer Study Group ; Medical Research Council UK [G117/569]
Funding Text:	Supported by Breakthrough Breast Cancer (project grant to T.S. and B.A.G.) and by the International Breast Cancer Study Group for production of the Trial V tissue array (BAG.). L.M.M. is funded by a Medical Research Council UK Senior Fellowship (G117/569).
Research teams:	Closed research groups > Cancer Genetics & Epigenetics
Depositing User:	Users 10 not found.
Date Deposited:	08 Dec 2010 16:41
Last Modified:	30 Aug 2011 15:41
URI:	http://publications.icr.ac.uk/id/eprint/10156

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