Bone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growth.
Bone morphogenetic proteins (BMPs) are multifunctional cytokines that regulate key developmental processes, but are also overexpressed in many carcinomas. To assess whether BMPs would influence the three-dimensional architecture of epithelial structures, we took advantage of an in vitro model in which mammary epithelial cells form alveolar-like spherical cysts in collagen gels. We found that BMP-4 has a dramatic, biphasic effect on the organization of epithelial cysts. When added in the concentration range of 1-10 ng/ml, the cytokine abrogates lumen formation and induces the outgrowth of multiple invasive cord-like structures. At higher concentrations (20-100 ng/ml), BMP-4 additionally disrupts cell-cell adhesion, resulting in cyst disintegration and scattering of individual cells into the surrounding collagen matrix. The finding that BMP-4 subverts the ability of mammary epithelial cells to form polarized lumen-containing structures and endows them with invasive properties supports the involvement of this cytokine in the progression of breast cancer.
Montesano
Roberto
R
Department of Cell Physiology and Metabolism, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland. Roberto.Montesano@medecine.unige.ch
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009570:Nitriles / Q000494:pharmacology
D000873:Anthracenes; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002070:Butadienes; D007093:Imidazoles; D009570:Nitriles; C113580:U 0126; C432165:pyrazolanthrone; D020928:Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole