title: MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells.
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.
authors.affiliation: Division of Experimental Oncology, Centre Pluridisciplinaire d'Oncologie, Lausanne Cancer Center, University of Lausanne, Epalinges, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Carrascosa
authors.forename: R G
authors.initials: RG
authors.lastname: Obula
authors.forename: E
authors.initials: E
authors.lastname: Missiaglia
authors.forename: H-A
authors.initials: HA
authors.lastname: Lehr
authors.forename: M
authors.initials: M
authors.lastname: Delorenzi
authors.forename: M
authors.initials: M
authors.lastname: Frattini
authors.forename: C
authors.initials: C
authors.lastname: Rüegg
authors.forename: A
authors.initials: A
authors.lastname: Mariotti
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D001940:Breast / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D056743:Cyclin D3 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008894:Milk Proteins; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000954:Antigens, Surface; D015820:Cadherins; D056743:Cyclin D3; C098942:MFGE8 protein, human; D008894:Milk Proteins; D019938:Cyclin D1