title: Augmented autocrine bone morphogenic protein (BMP) 7 signaling increases the metastatic potential of mouse breast cancer cells.
abstract: As malignant breast cancers progress, they acquire the ability to spread to other regions of the body, including bone and lung, but the molecular mechanism underlying the increase in metastatic potential is not fully understood. Here we studied murine 4T1E/M3 highly bone marrow metastatic breast cancer cells, which we established previously. These cells show upregulated expression of bone morphogenetic protein (BMP) 7 and BMP receptors, as well as augmented phosphorylation of Smad1/5/8. Both anchorage-independent cell growth measured in colony forming assays and cell migration measured in wound healing assays were suppressed in 4T1E/M3 cells following treatment with a neutralizing anti-BMP7 antibody or knockdown of BMP7 gene expression. In addition, metastasis of 4T1E/M3 cells to the spine and lung and intracellular levels of phosphorylated Smad1/5/8 were suppressed by knocking down BMP7. Conversely, overexpression of BMP7 in the weakly metastatic parental 4T1E cells augmented their anchorage-independent growth, migration and metastasis to spine and lung. Taken together, our results strongly suggest that augmented autocrine BMP7 signaling leads to increases in the anchorage-independent cell growth, migration and metastatic potential in our bone marrow metastatic breast cancer model.
authors.affiliation: Signaling Molecules Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, 1-1-1, Higashi, Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sakai
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
authors.forename: Chie
authors.initials: C
authors.lastname: Matsuda
authors.forename: Munehisa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Takeo
authors.initials: T
authors.lastname: Konakahara
authors.forename: Toru
authors.initials: T
authors.lastname: Imamura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Okada
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D019046:Bone Marrow Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D014407:Tumor Cells, Cultured
chemical_list: D055419:Bone Morphogenetic Protein 7; C525820:bmp7 protein, mouse