title: BMP-6 inhibits the metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression.
abstract: Bone morphogenetic protein-6 (BMP-6) is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis. In the present study, our results showed that the rate of BMP-6-negative expression was 30.56% in breast cancer tissues, but was 9.58% in normal tissues by immunohistochemical staining. This implied that BMP-6 expression is absent in breast cancer tissues and may suppress breast cancer metastasis. In addition, stable overexpression of BMP-6 in MDA-MB‑231 cells was established to analyze the metastatic ability. The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MDA-MB-231 cells. Moreover, real-time PCR analysis showed that BMP-6 markedly downregulated matrix metalloproteinase-1 (MMP-1) expression at both the mRNA and protein levels in the MDA-MB‑231 cells. Importantly, the results of luciferase and CHIP assays revealed that BMP-6 inhibited MMP-1 promoter activity through the AP-1 response element. In MDA-MB-231 cells treated with BMP-6, a significant decrease in the recruitment of AP-1 components, c-Jun/c-Fos, to the endogenous MMP-1 promoter was noted. We also demonstrated that BMP-6 inhibited the invasion of MDA-MB-231 cells, and this effect was significantly attenuated by overexpression of MMP-1. In contrast, MMP-1 knockdown by RNA interference or MMP-1 inhibitor exhibited an opposite effect. These observations suggest a novel role of BMP-6 in the inhibition of breast cancer metastasis by regulating secretion of MMPs in the tumor microenvironment.
authors.affiliation: College of Life Sciences, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Fen
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Life Sciences, Tangshan Normal University, Tangshan, Hebei 063000, P.R. China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.affiliation: College of Life Sciences, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.affiliation: College of Life Sciences, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Medical College of Nankai University, Tianjin 300071, P.R. China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: College of Psychology, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Zhang
mesh_terms: D055418:Bone Morphogenetic Protein 6 / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1