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. 2012 Mar 22;31(12):1521-32.
doi: 10.1038/onc.2011.356. Epub 2011 Aug 15.

MFG-E8/lactadherin Regulates Cyclins D1/D3 Expression and Enhances the Tumorigenic Potential of Mammary Epithelial Cells

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MFG-E8/lactadherin Regulates Cyclins D1/D3 Expression and Enhances the Tumorigenic Potential of Mammary Epithelial Cells

C Carrascosa et al. Oncogene. .

Abstract

Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein highly expressed in breast cancer that contributes to tumor progression through largely undefined mechanisms. By analyzing publicly available gene expression profiles of breast carcinomas, we found that MFG-E8 is highly expressed in primary and metastatic breast carcinomas, associated with absent estrogen receptor expression. Immunohistochemistry analysis of breast cancer biopsies revealed that MFG-E8 is expressed on the cell membrane as well as in the cytoplasm and nucleus. We also show that increased expression of MFG-E8 in mammary carcinoma cells increases their tumorigenicity in immunodeficient mice, and conversely, its downregulation reduces their in vivo growth. Moreover, expression of MFG-E8 in immortalized mammary epithelial cells promotes their growth and branching in three-dimensional collagen matrices and induces the expression of cyclins D1/D3 and N-cadherin. A mutant protein unable to bind integrins can in part exert these effects, indicating that MFG-E8 function is only partially dependent on integrin activation. We conclude that MFG-E8-dependent signaling stimulates cell proliferation and the acquisition of mesenchymal properties and contributes to mammary carcinoma development.

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