title: The metastasis-promoting protein S100A4 regulates mammary branching morphogenesis.
abstract: High levels of the S100 calcium binding protein S100A4 also called fibroblast specific protein 1 (FSP1) have been established as an inducer of metastasis and indicator of poor prognosis in breast cancer. The mechanism by which S100A4 leads to increased cancer aggressiveness has yet to be established; moreover, the function of this protein in normal mammary gland biology has not been investigated. To address the role of S100A4 in normal mammary gland, its spatial and temporal expression patterns and possible function in branching morphogenesis were investigated. We show that the protein is expressed mainly in cells of the stromal compartment of adult humans, and during active ductal development, in pregnancy and in involution of mouse mammary gland. In 3D culture models, topical addition of S100A4 induced a significant increase in the TGFα mediated branching phenotype and a concomitant increase in expression of a previously identified branching morphogen, metalloproteinase-3 (MMP-3). These events were found to be dependent on MEK activation. Downregulation of S100A4 using shRNA significantly reduced TGFα induced branching and altered E-cadherin localization. These findings provide evidence that S100A4 is developmentally regulated and that it plays a functional role in mammary gland development, in concert with TGFα by activating MMP-3, and increasing invasion into the fat pad during branching. We suggest that S100A4-mediated effects during branching morphogenesis provide a plausible mechanism for how it may function in breast cancer progression.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. kristin.andersen@rr-research.no
authors.forename: Kristin
authors.initials: K
authors.lastname: Andersen
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Mori
authors.forename: Jimmie
authors.initials: J
authors.lastname: Fata
authors.forename: Jamie
authors.initials: J
authors.lastname: Bascom
authors.forename: Tove
authors.initials: T
authors.lastname: Oyjord
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.forename: Mina
authors.initials: M
authors.lastname: Bissell
mesh_terms: D000818:Animals; D001483:Base Sequence; D001940:Breast / Q000254:growth & development*; D001943:Breast Neoplasms / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009024:Morphogenesis; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D011247:Pregnancy; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C077591:S100A4 protein, human; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse